Comprehensive Physiology Wiley Online Library

Insulin‐Like Growth Factors: Gene Structure and Regulation

Full Article on Wiley Online Library



Abstract

The sections in this article are:

1 Insulin‐Like Growth Factor I
1.1 Insulin‐Like Growth Factor I cDNAs and Encoded Precursors
1.2 Multiple Insulin‐Like Growth Factor I mRNAs and Precursors in Mammals
1.3 Multiple Size Classes of Insulin‐Like Growth Factor I mRNAs
1.4 Insulin‐Like Growth Factor I Gene Structure
1.5 Functional Significance of Multiple Mammalian Insulin‐Like Growth Factor I mRNAs and Precursors
1.6 Insulin‐Like Growth Factor I mRNA Regulation
1.7 Structure And Regulation of the Insulin‐Like Growth Factor I Promoters
2 Insulin‐Like Growth Factor II
2.1 Insulin‐Like Growth Factor II cDNAs and Encoded Precursors
2.2 Multiple Insulin‐Like Growth Factor II mRNAs
2.3 Insulin‐Like Growth Factor II Gene Structure
2.4 Insulin‐Like Growth Factor II mRNA Regulation
2.5 Transcriptional Control of Insulin‐Like Growth Factor II Synthesis
2.6 Post‐Transcriptional Control of Insulin‐Like Growth Factor II Synthesis
3 Manipulation of the Expression of Insulinlike Growth Factors I and II
3.1 Gain of Function Insulin‐Like Growth Factor Transgenics
3.2 Loss of Function Insulin‐Like Growth Factor Transgenics
3.3 Chimeric Genes and Insulin‐Like Growth Factor Gene Regulation
4 Future Directions
Figure 1. Figure 1.

Comparison of amino‐acid sequences of human proinsulin, insulin‐like growth factors I and II, (IGF‐I and IGF‐II). Amino acids, in single letter code, are aligned to show regions of homology. Regions of homology are boxed. Peptide domains are identified by the letter above each group.

Figure 2. Figure 2.

Schematic of structure of isolated mammalian insulin‐like growth factor I (IGF‐I) cDNAs to illustrate mRNA and precursor heterogeneity. Open bar shows identical coding sequence in all isolated IGF‐I cDNAs; shaded bar indicates distinct 5′ sequences in class 1 or class 2 IGF‐I cDNAs that specify variable leader peptide and/or 5′UT and distinct 3′ sequences on Ea and Eb type cDNAs that encode different E domains and 3′UT.

Figure 3. Figure 3.

Evolutionary conservation of insulin‐like growth factor I (IGF‐I) precursor sequences. a: Comparison of amino‐acid sequences of mature IGF‐I peptides in several species. Dashes indicate identical amino acids. b: Comparisons of precursor peptide sequences (class 1 or class 2 leader peptides and Ea or Eb domains) predicted by isolated IGF‐I cDNAs. Cow and sheep class 1 and class 2 leader peptides are prefixed with an asterisk, because a glutamine (Q) residue has been omitted to maximize alignment with leader peptides from other species. Asterisks above class 1 and class 2 leader peptides indicate methionine residues common to both coding sequences. Note that the first 16 amino acids shown for the COOH terminal Ea and Eb domains are identical, followed by the distinct precursor peptides. In the salmon Ea domain, 27 amino acids were deleted to maximize homology with the Ea domains of other species.

Figure 4. Figure 4.

Autoradiograms of RNase protection and Northern hybridization assays to illustrate tissue‐specific expression of insulin‐like growth factor I mRNA subtypes. A: RNAse protection shows expression of class 1 and class 2 IGF‐I mRNAs in rat liver and low or barely detectable expression in nonhepatic tissues such as brain and ileum. B: Northern hybridization with probes specific for class 1, class 2, Ea, or Eb type on RNA from adult rat liver illustrates the size heterogeneity of each IGF‐I mRNA sub‐type.

Figure 5. Figure 5.

Structure of human and rat insulin‐like growth factor I (IGF‐I) genes. Schematic to show human (top) and rat (bottom) IGF‐I gene structure. Solid boxes indicate the exons common to all characterized human or rat IGF‐I mRNAs. Open boxes indicate exons that are alternately spliced. Alternate splicing of exons 1, 2, 5, and 6 that leads to four potential mRNA coding sequences for human or rat IGF‐I precursors is indicated.

Figure 6. Figure 6.

Schematic of the transcription starts sites and characterized gene regulatory regions in human and rat insulin‐like growth factor I (IGF‐I) genes. a: Top panel shows a schematic of exons 1–3, introns 1 and 2, and 5′ flanking sequence in human and rat IGF‐I genes. Major (tall arrows) and minor (short arrows) transcription start sites are shown together with translation initiation AUG/Met codons that would be included in derived mRNAs as a result of use of alternate transcription start sites. Open arrow indicates a proximal transcription start site mapped only in exon 1 of the rat IGF‐I gene that would exclude AUG/Met codon −48 from the derived mRNA . A DNase 1 hypersensitive site in intron 2, HS7, that is associated with growth hormone (GH) induction of the IGF‐I gene is also shown in the line underneath intron 2 . // indicates that size of introns 1 and 2 is not to scale relative to the size of the exons. Bottom panel shows expanded view of exon 1 and 5′ flanking DNA to indicate the major regions implicated as cis‐acting regulatory sequences and binding sites for transcription factors. Scale above the sequence is in nucleotides. The first base of the most downstream major transcription start site in human and rat IGF‐I genes is designated +1. Upstream and downstream regions are indicated by negative and positive numbers, respectively. The location of this major transcription start site relative to other transcription start sites is indicated by the tall and short arrows above the scale, as also indicated in the top panel. The transcribed portion of exon 1 is indicated by the wide bar and the nontranscribed flanking region by the narrow bar. Binding of transcription factors HNF‐3β, HNF‐1α, and C/EBPα to the indicated regions and functional transcriptional activation have been documented only for the human IGF‐I gene . Open triangles (numbered 1–4) are regions that confer liver‐specific transcriptional activation of rat promoter 1 in an in vitro transcription system . FP1 indicates region of rat exon 1 defined as a major transcription regulatory sequence and site of protein binding in C6 glioma cells . HS3A, HS3B, and HS3C indicate the location of 3 DNase I footprints in rat IGF‐I gene implicated as sites of DNA: protein interaction during GH activation of the IGF‐I gene in rat liver . Labeled line beneath indicates location of two DNase I hypersensitive sites implicated in developmental induction of hepatic IGF‐I gene expression in the rat . The overlap in gene regulatory elements in human and rat IGF‐I genes defined by multiple different approaches and in multiple systems indicates a growing consensus about molecular mechanisms of transcriptional activation of promoter 1. B: Summary of sequences in human and rat IGF‐I exon 1 and 5′ flanking DNA corresponding to the predicted locations of gene regulatory elements and sites of transcription factor binding. The location of each sequence is indicated in nucleotides upstream (‐) or downstream (+) of the downstream major transcription site in human or rat exons 1 designated +1 in Figure A. In the original reports describing these sites, not all authors use this site as +1 and so their numerical designation may differ from that used here. The transcription factors indicated in parentheses correspond to factors with consensus binding sites that show some degree of homology with the putative gene regulatory elements.

Figure 7. Figure 7.

Comparison of amino acid sequences of insulin‐like growth factor II (IGF‐II) precursors from several species. Dashes indicate identical amino acids compared with human precursor.

Figure 8. Figure 8.

Comparison of the rat and human insulin‐like growth factor II (IGF‐II) genes. Solid bars indicate coding exons for IGF‐II precursor. Open bars indicate exons that specify 5′ or 3′ UTs. Alternate splicing of human exons 1–6 that leads to human IGF‐II mRNAs that differ in 5′ UT and size is indicated. The 1.8 kb mRNA fragment is comprised entirely of exon 9 sequence. In the human gene, hP1–hP4 indicate four promoters that control expression of different IGF‐II mRNAs. In the rat, promoters rP1, rP2, and rP3 are counterparts of hP2, hP3, and hP4, respectively. ins indicates the insulin gene that lies close to the IGF‐II gene in human and rat.

Figure 9. Figure 9.

A schematic of human insulin‐like growth factor II (IGF‐II) promoter 3 and putative gene regulatory regions. Binding sites for EGR and WT1 transcription factors are shown together with important sites of DNA: protein interaction mapped by DNase footprinting, gel shift, or in vitro trancription (PE3‐1‐PE3‐4) .

Figure 10. Figure 10.

“Enhancer competition” model of insulin‐like growth factor II (IGF‐II) imprinting. Top: Schematic of IGF‐II and H19 locus in wild‐type mouse showing two distal enhancers (•) downstream of H19. On the paternal allele, shading indicates methylation of 5′ portion of H19 gene. Large arrows indicate transcription of IGF‐II gene from the paternal allele and H19 from the maternal allele as indicated in figure on right. Middle: Schematic of the consequences of deletion of enhancers on maternal allele as reported in . No effect on IGF‐II expression from paternal allele but decreased expression of H19 from maternal allele as indicated. Bottom: Schematic of consequences of deletion of enhancers on paternal allele as reported in . IGF‐II expression from paternal allele is decreased whereas expression of H19 from maternal allele is unaffected.



Figure 1.

Comparison of amino‐acid sequences of human proinsulin, insulin‐like growth factors I and II, (IGF‐I and IGF‐II). Amino acids, in single letter code, are aligned to show regions of homology. Regions of homology are boxed. Peptide domains are identified by the letter above each group.



Figure 2.

Schematic of structure of isolated mammalian insulin‐like growth factor I (IGF‐I) cDNAs to illustrate mRNA and precursor heterogeneity. Open bar shows identical coding sequence in all isolated IGF‐I cDNAs; shaded bar indicates distinct 5′ sequences in class 1 or class 2 IGF‐I cDNAs that specify variable leader peptide and/or 5′UT and distinct 3′ sequences on Ea and Eb type cDNAs that encode different E domains and 3′UT.



Figure 3.

Evolutionary conservation of insulin‐like growth factor I (IGF‐I) precursor sequences. a: Comparison of amino‐acid sequences of mature IGF‐I peptides in several species. Dashes indicate identical amino acids. b: Comparisons of precursor peptide sequences (class 1 or class 2 leader peptides and Ea or Eb domains) predicted by isolated IGF‐I cDNAs. Cow and sheep class 1 and class 2 leader peptides are prefixed with an asterisk, because a glutamine (Q) residue has been omitted to maximize alignment with leader peptides from other species. Asterisks above class 1 and class 2 leader peptides indicate methionine residues common to both coding sequences. Note that the first 16 amino acids shown for the COOH terminal Ea and Eb domains are identical, followed by the distinct precursor peptides. In the salmon Ea domain, 27 amino acids were deleted to maximize homology with the Ea domains of other species.



Figure 4.

Autoradiograms of RNase protection and Northern hybridization assays to illustrate tissue‐specific expression of insulin‐like growth factor I mRNA subtypes. A: RNAse protection shows expression of class 1 and class 2 IGF‐I mRNAs in rat liver and low or barely detectable expression in nonhepatic tissues such as brain and ileum. B: Northern hybridization with probes specific for class 1, class 2, Ea, or Eb type on RNA from adult rat liver illustrates the size heterogeneity of each IGF‐I mRNA sub‐type.



Figure 5.

Structure of human and rat insulin‐like growth factor I (IGF‐I) genes. Schematic to show human (top) and rat (bottom) IGF‐I gene structure. Solid boxes indicate the exons common to all characterized human or rat IGF‐I mRNAs. Open boxes indicate exons that are alternately spliced. Alternate splicing of exons 1, 2, 5, and 6 that leads to four potential mRNA coding sequences for human or rat IGF‐I precursors is indicated.



Figure 6.

Schematic of the transcription starts sites and characterized gene regulatory regions in human and rat insulin‐like growth factor I (IGF‐I) genes. a: Top panel shows a schematic of exons 1–3, introns 1 and 2, and 5′ flanking sequence in human and rat IGF‐I genes. Major (tall arrows) and minor (short arrows) transcription start sites are shown together with translation initiation AUG/Met codons that would be included in derived mRNAs as a result of use of alternate transcription start sites. Open arrow indicates a proximal transcription start site mapped only in exon 1 of the rat IGF‐I gene that would exclude AUG/Met codon −48 from the derived mRNA . A DNase 1 hypersensitive site in intron 2, HS7, that is associated with growth hormone (GH) induction of the IGF‐I gene is also shown in the line underneath intron 2 . // indicates that size of introns 1 and 2 is not to scale relative to the size of the exons. Bottom panel shows expanded view of exon 1 and 5′ flanking DNA to indicate the major regions implicated as cis‐acting regulatory sequences and binding sites for transcription factors. Scale above the sequence is in nucleotides. The first base of the most downstream major transcription start site in human and rat IGF‐I genes is designated +1. Upstream and downstream regions are indicated by negative and positive numbers, respectively. The location of this major transcription start site relative to other transcription start sites is indicated by the tall and short arrows above the scale, as also indicated in the top panel. The transcribed portion of exon 1 is indicated by the wide bar and the nontranscribed flanking region by the narrow bar. Binding of transcription factors HNF‐3β, HNF‐1α, and C/EBPα to the indicated regions and functional transcriptional activation have been documented only for the human IGF‐I gene . Open triangles (numbered 1–4) are regions that confer liver‐specific transcriptional activation of rat promoter 1 in an in vitro transcription system . FP1 indicates region of rat exon 1 defined as a major transcription regulatory sequence and site of protein binding in C6 glioma cells . HS3A, HS3B, and HS3C indicate the location of 3 DNase I footprints in rat IGF‐I gene implicated as sites of DNA: protein interaction during GH activation of the IGF‐I gene in rat liver . Labeled line beneath indicates location of two DNase I hypersensitive sites implicated in developmental induction of hepatic IGF‐I gene expression in the rat . The overlap in gene regulatory elements in human and rat IGF‐I genes defined by multiple different approaches and in multiple systems indicates a growing consensus about molecular mechanisms of transcriptional activation of promoter 1. B: Summary of sequences in human and rat IGF‐I exon 1 and 5′ flanking DNA corresponding to the predicted locations of gene regulatory elements and sites of transcription factor binding. The location of each sequence is indicated in nucleotides upstream (‐) or downstream (+) of the downstream major transcription site in human or rat exons 1 designated +1 in Figure A. In the original reports describing these sites, not all authors use this site as +1 and so their numerical designation may differ from that used here. The transcription factors indicated in parentheses correspond to factors with consensus binding sites that show some degree of homology with the putative gene regulatory elements.



Figure 7.

Comparison of amino acid sequences of insulin‐like growth factor II (IGF‐II) precursors from several species. Dashes indicate identical amino acids compared with human precursor.



Figure 8.

Comparison of the rat and human insulin‐like growth factor II (IGF‐II) genes. Solid bars indicate coding exons for IGF‐II precursor. Open bars indicate exons that specify 5′ or 3′ UTs. Alternate splicing of human exons 1–6 that leads to human IGF‐II mRNAs that differ in 5′ UT and size is indicated. The 1.8 kb mRNA fragment is comprised entirely of exon 9 sequence. In the human gene, hP1–hP4 indicate four promoters that control expression of different IGF‐II mRNAs. In the rat, promoters rP1, rP2, and rP3 are counterparts of hP2, hP3, and hP4, respectively. ins indicates the insulin gene that lies close to the IGF‐II gene in human and rat.



Figure 9.

A schematic of human insulin‐like growth factor II (IGF‐II) promoter 3 and putative gene regulatory regions. Binding sites for EGR and WT1 transcription factors are shown together with important sites of DNA: protein interaction mapped by DNase footprinting, gel shift, or in vitro trancription (PE3‐1‐PE3‐4) .



Figure 10.

“Enhancer competition” model of insulin‐like growth factor II (IGF‐II) imprinting. Top: Schematic of IGF‐II and H19 locus in wild‐type mouse showing two distal enhancers (•) downstream of H19. On the paternal allele, shading indicates methylation of 5′ portion of H19 gene. Large arrows indicate transcription of IGF‐II gene from the paternal allele and H19 from the maternal allele as indicated in figure on right. Middle: Schematic of the consequences of deletion of enhancers on maternal allele as reported in . No effect on IGF‐II expression from paternal allele but decreased expression of H19 from maternal allele as indicated. Bottom: Schematic of consequences of deletion of enhancers on paternal allele as reported in . IGF‐II expression from paternal allele is decreased whereas expression of H19 from maternal allele is unaffected.

References
 1. Acland, P., M. Dixon, G. Peters, and C. Dickson. Subcellular fate of the int‐2 oncoprotein is determined by choice of initiation codon. Nature 343: 662–665, 1990.
 2. Acquaviva, A. M., C. B. Bruni, S. P. Nissley, and M. M. Rechler. Cell‐free synthesis of rat insulin‐like growth factor II. Diabetes 31: 656–658, 1982.
 3. Adamo, M. L., H. Ben‐Hur, C. T. Roberts, Jr., and D. LeRoith. Regulation of start site usage in the leader exons of the rat insulin‐like growth factor‐I gene by development, fasting, and diabetes. Mol. Endocrinol. 5: 1677–1686, 1991.
 4. Adamo, M. L., F. Lanau, S. Neuenschwander, H. Werner, D. LeRoith, and C. T. Roberts, Jr. Distinct promoters in the rat insulin‐like growth factor‐I (IGF‐I) gene are active in CHO cells [published erratum appears in Endocrinology 133: 792, 1993]. Endocrinology 132: 935–937, 1993.
 5. Adashi, E. Y. Growth factors and ovarian function: the IGF‐I paradigm. Horm. Res. 42: 44–48, 1994.
 6. An, M. R., and W. L. Lowe, Jr. The major promoter of the rat insulin‐like growth factor‐I gene binds a protein complex that is required for basal expression. Mol. Cell. Endocrinol. 114: 77–89, 1995.
 7. Arany, E., A. J. Strain, M. J. Hube, I. D. Phillips, and D. J. Hill. Interactive effects of nutrients and hormones on the expression of insulin‐like growth factor binding protein‐1 (IGFBP‐1) mRNA and peptide, and IGF I release from isolated adult rat hepatocytes. J. Cell. Physiol. 155: 426–135, 1993.
 8. Arkins, S., N. Rebeiz, A. Biragyn, D. L. Reese, and K. W. Kelley. Murine macrophages express abundant insulin‐like growth factor‐I class I Ea and Eb transcripts. Endocrinology 133: 2334–2343, 1993.
 9. Arkins, S., N. Rebeiz, D. L. Brunke‐Reese, A. Biragyn, and K. W. Kelley. Interferon‐gamma inhibits macrophage insulin‐like growth factor‐I synthesis at the transcriptional level. Mol. Endocrinol. 9: 350–360, 1995.
 10. Arkins, S., N. Rebeiz, D. L. Brunke‐Reese, C. Minshall, and K. W. Kelley. The colony‐stimulating factors induce expression of insulin‐like growth factor I messenger ribonucleic acid during hematopoiesis. Endocrinology 136: 1153–1160, 1995.
 11. Bach, M. A., C. T. Roberts, Jr., E. P. Smith, and D. LeRoith. Alternative splicing produces messenger RNAs encoding insulin‐like growth factor‐I prohormones that are differentially glycosylated in vitro. Mol. Endocrinol. 4: 899–904, 1990.
 12. Baker, J., J. P. Liu, E. J. Robertson, and A. Efstratiadis. Role of insulin‐like growth factors in embryonic and postnatal growth. Cell 75: 73–82, 1993.
 13. Barlow, D. P. Methylation and imprinting: from host defense to gene regulation? Science 260: 309–310, 1993.
 14. Barlow, D. P. Imprinting: a gamete's point of view. Trends Genet. 10: 194–199, 1994.
 15. Bartolomei, M. S., A. L. Webber, M. E. Brunkow, and S. M. Tilghman. Epigenetic mechanisms underlying the imprinting of the mouse H19 gene. Genes Dev. 7: 1663–1673, 1993.
 16. Behringer, R. R., T. M. Lewin, C. J. Quaife, R. D. Palmiter, R. L. Brinster, and A. J. D'Ercole. Expression of insulin‐like growth factor I stimulates normal somatic growth in growth hormone‐deficient transgenic mice. Endocrinology 127: 1033–1040, 1990.
 17. Beilharz, E. J., N. S. Bassett, E. S. Sirimanne, C. E. Williams, and P. D. Gluckman. Insulin‐like growth factor II is induced during wound repair following hypoxic‐ischemic injury in the developing rat brain. Brain Res./Mol. Brain Res. 29: 81–91, 1995.
 18. Bell, G. I., D. S. Gerhard, N. M. Fong, R. Sanchez‐Pescador, and L. B. Rall. Isolation of the human insulin‐like growth factor genes: insulin‐like growth factor II and insulin genes are contiguous. Proc. Natl. Acad. Sci. USA 82: 6450–6454, 1985.
 19. Bell, G. I., J. P. Merryweather, R. Sanchez‐Pescador, et al. Sequence of a cDNA clone encoding human preproinsulin‐like growth factor II. Nature 310: 775–777, 1984.
 20. Bell, G. I., M. M. Stempien, N. M. Fong, and L. B. Rall. Sequences of liver cDNAs encoding two different mouse insulinlike growth factor I precursors. Nucleic Acids Res. 14: 7873–7882, 1986.
 21. Bell, G. I., M. M. Stempien, N. M. Fong, and S. Seino. Sequence of a cDNA encoding guinea pig IGF‐I. Nucleic Acids Res. 18: 4275, 1990.
 22. Bichell, D. P., K. Kikuchi, and P. Rotwein. Growth hormone rapidly activates insulin‐like growth factor I gene transcription in vivo. Mol. Endocrinol. 6: 1899–1908, 1992.
 23. Bichell, D. P., P. Rotwein, and T. L. McCarthy. Prostaglandin E2 rapidly stimulates insulin‐like growth factor‐I gene expression in primary rat osteoblast cultures: evidence for transcriptional control. Endocrinology 133: 1020–1028, 1993.
 24. Bickmore, W. A., K. Oghene, M. H. Little, A. Seawright, and V. van Heyningen. Modulation of DNA binding specificity by alternative splicing of the Wilms tumor wt1 gene transcript. Science 257: 235–237, 1992.
 25. Birkenmeier, E. H., B. Gwynn, S. Howard, J. Jerry, J. I. Gordon, and W. H. M. K. Landschulz. Tissue‐specific expression, developmental regulation, and genetic mapping of the gene encoding CCAAT/enhancer binding protein. Genes Dev. 3: 1146–1156, 1989.
 26. Blumenfeld, M., M. Maury, T. Chouard, M. Yaniv, and H. Condamine. Hepatic nuclear factor 1 (HNF1) shows a wider distribution than products of its known target genes in developing mouse. Development 113: 589–599, 1991.
 27. Bondy, C. A., H. Werner, C. T. Roberts, Jr., and D. LeRoith. Cellular pattern of insulin‐like growth factor‐I (IGF‐I) and type I IGF receptor gene expression in early organogenesis: comparison with IGF‐II gene expression. Mol. Endocrinol. 4: 1386–1398, 1990.
 28. Boni‐Schnetzler, M., C. Schmid, P. J. Meier, and E. R. Froesch. Insulin regulates insulin‐like growth factor I mRNA in rat hepatocytes. Am. J. Physiol. 260 (Endocrinol. Metab. 23): E846–E851, 1991.
 29. Bornfeldt, K. E., H. J. Arnqvist, B. Enberg, L. S. Mathews, and G. Norstedt. Regulation of insulin‐like growth factor‐I and growth hormone receptor gene expression by diabetes and nutritional state in rat tissues. J. Endocrinol. 122: 651–656, 1989.
 30. Botero, L. F., C. T. Roberts, Jr., D. LeRoith, E. Y. Adashi, and E. R. Hernandez. Insulin‐like growth factor I gene expression by primary cultures of ovarian cells: insulin and dexamethasone dependence. Endocrinology 132: 2703–2708, 1993.
 31. Brandeis, M., T. Kafri, M. Ariel, J. R. Chaillet, J. McCarrey, and A. Razin. The ontogeny of allele‐specific methylation associated with imprinted genes in the mouse. EMBO J. 12: 3669–3677, 1993.
 32. Brown, A. L., D. E. Graham, S. P. Nissley, D. J. Hill, A. J. Strain, and M. M. Rechler. Developmental regulation of insulin‐like growth factor II mRNA in different rat tissues. J. Biol. Chem. 261: 13144–13150, 1986.
 33. Brown, W. M., K. M. Dziegielewska, R. C. Foreman, and N. R. Saunders. The nucleotide and deduced amino acid sequences of insulin‐like growth factor II cDNAs from adult bovine and fetal sheep liver. Nucleic Acids Res. 18: 4614, 1990.
 34. Bucci, C., P. Mallucci, C. T. Roberts, R. Frunzio, and C. B. Bruni. Nucleotide sequence of a genomic fragment of the rat IGF‐I gene spanning an alternate 5′non coding exon. Nucleic Acids Res. 17: 3596, 1989.
 35. Cao, Q. P., S. J. Duguay, E. Plisetskaya, D. F. Steiner, and S. J. Chan. Nucleotide sequence and growth hormone‐regulated expression of salmon insulin‐like growth factor I mRNA. Mol. Endocrinol. 3: 2005–2010, 1989.
 36. Cao, Z., R. M. Umek, and S. L. McKnight. Regulated expression of three C/EBP isoforms during adipose conversion of 3T3–L1 cells. Genes Dev. 5: 1538–1552, 1991.
 37. Carlsson‐Skwirut, C., M. Lake, M. Hartmanis, K. Hall, and V. R. Sara. A comparison of the biological activity of the recombinant intact and truncated insulin‐like growth factor I (IGF‐I). Biochim. Biophys. Acta 1011: 192–197, 1989.
 38. Carter‐Su, C., L. S. Argetsinger, G. S. Campbell, X. Wang, J. Ihle, and B. Witthuhn. The identification of JAK2 tyrosine kinase as a signaling molecule for growth hormone. Proc. Soc. Exp. Biol. Med. 206: 210–215, 1994.
 39. Cascieri, M. A., and M. L. Bayne. Identification of the domains of IGF‐I which interact with the IGF receptors and binding proteins. In: Molecular and Cellular Biology of Insulin‐Like Growth Factors and Their Receptors, edited by D. LeRoith and M. K. Raizada. New York: Plenum Press, 1989, p. 285–297.
 40. Casella, S. J., E. P. Smith, J. J. van Wyk, et al. Isolation of rat testis cDNAs encoding an insulin‐like growth factor I precursor. DNA 6: 325–330, 1987.
 41. Chiariotti, L., A. L. Brown, R. Frunzio, D. R. Clemmons, M. M. Rechler, and C. B. Bruni. Structure of the rat insulinlike growth factor II transcriptional unit: heterogeneous transcripts are generated from two promoters by use of multiple polyadenylation sites and differential ribonucleic acid splicing. Mol. Endocrinol. 2: 1115–1126, 1988.
 42. Christofori, G., P. Naik, and D. Hanahan. A second signal supplied by insulin‐like growth factor II in oncogene‐induced tumorigenesis. Nature 369: 414–418, 1994.
 43. Clayton, P. E., R. N. Day, C. M. Silva, P. Hellmann, K. H. Day, and M. O. Thorner. Growth hormone induces tyrosine phosphorylation but does not alter insulin‐like growth factor‐I gene expression in human IM9 lymphocytes. J. Mol. Endocrinol. 13: 127–136, 1994.
 44. Clemmons, D. R., and D. S. Shaw. Purification and biologic properties of fibroblast somatomedin. J. Biol. Chem. 261: 10293–10298, 1986.
 45. Cohen, J. A., E. M. Zimmermann, R. B. Sartor, and P. K. Lund. IGF‐I and IGF‐II are overexpressed in inflamed and strictured intestine in Crohn's disease. Gastroenterology 104: A683, 1993.
 46. Coleman, M. E., F. DeMayo, K. C. Yin, H. M. Lee, R. Geske, and C. Montgomery. Myogenic vector expression of insulinlike growth factor I stimulates muscle cell differentiation and myofiber hypertrophy in transgenic mice. J. Biol. Chem. 270: 12109–12116, 1995.
 47. Conover, C. A., B. K. Baker, and R. L. Hintz. Cultured human fibroblasts secrete insulin‐like growth factor IA prohormone. J. Clin. Endocrinol. Metab. 69: 25–30, 1989.
 48. Culouscou, J. M., M. Remacle‐Bonnet, F. Garrouste, J. Fantini, J. Marvaldi, and G. Pommier. Production of insulin‐like growth factor II (IGF‐II) and different forms of IGF‐binding proteins by HT‐29 human colon carcinoma cell line. J. Cell. Physiol. 143: 405–415, 1990.
 49. D'Ercole, A. J. Expression of insulin‐like growth factor‐I in transgenic mice. Ann. NY Acad. Sci. 692: 149–160, 1993.
 50. D'Ercole, A. J., G. T. Applewhite, and L. E. Underwood. Evidence that somatomedin is synthesized by multiple tissues in the fetus. Dev. Biol. 75: 315–328, 1980.
 51. D'Ercole, A. J., A. D. Stiles, and L. E. Underwood. Tissue concentrations of somatomedin C: further evidence for multiple sites of synthesis and paracrine or autocrine mechanisms of action. Proc. Natl. Acad. Sci. USA 81: 935–939, 1984.
 52. D'Ercole, A. J., P. Ye, A. S. Calikoglu, and G. Gutierrez‐Ospina. The role of the insulin‐like growth factors in the central nervous system. Mol. Neurobiol. 13: 227–255, 1996.
 53. Daughaday, W. H. The possible autocrine/paracrine and endocrine roles of insulin‐like growth factors of human tumors. Endocrinology 127: 1–4, 1990.
 54. Daughaday, W. H., K. A. Parker, S. Borowsky, B. Trivedi, and M. Kapadia. Measurement of somatomedin‐related peptides in fetal, neonatal, and maternal rat serum by insulin‐like growth factor (IGF) I radioimmunoassay, IGF‐II radioreceptor assay (RRA), and multiplication‐stimulating activity RRA after acid‐ethanol extraction. Endocrinology 110: 575–581, 1982.
 55. Davenport, M. L., D. Novotny, and B. Li. Complementary localization of IGF‐IA and IGF‐IB propeptides throughout rat uteroplacental development. Endocrine Society 77th Annual Meeting Abstract P2–307, 1995.
 56. de Moor, C. H., M. Jansen, E. J. Bonte, A. A. Thomas, J. S. Sussenbach, and J. L. Van DenBrande. Influence of the four leader sequences of the human insulin‐like‐growth‐factor‐2 mRNAs on the expression of reporter genes. Eur. J. Biochem. 226: 1039–1047, 1994.
 57. de Moor, C. H., M. Jansen, E. J. Bonte, A. A. Thomas, J. S. Sussenbach, and J. L. Van DenBrande. Proteins binding to the leader of the 6.0 kb mRNA of human insulin‐like growth factor 2 influence translation. Biochem. J. 307: 225–231, 1995.
 58. de Moor, C. H., M. Jansen, J. S. Sussenbach, and J. L. Van den Brande. Differential polysomal localization of human insulin‐like‐growth‐factor‐2 mRNAs in cell lines and foetal liver. Eur. J. Biochem. 222: 1017–1024, 1994.
 59. de Pagter‐Holthuizen, P., M. Jansen, F. M. van Schaik, R. van der Kammen, J. L. Van den Brande, and J. S. Sussenbach. The human insulin‐like growth factor II gene contains two development‐specific promoters. FEBS Lett. 214: 259–264, 1987.
 60. de Pagter‐Holthuizen, P., F. M. van Schaik, G. M. Verduijn, G. J. van Ommen, M. Jansen, and J. S. Sussenbach. Organization of the human genes for insulin‐like growth factors I and II. FEBS Lett. 195: 179–184, 1986.
 61. De Simone, V., and R. Cortese. Transcription factors and liver‐specific genes. Biochim. Biophys. Acta 1132: 119–126, 1992.
 62. DeChiara, T. M., A. Efstratiadis, and E. J. Robertson. A growth‐deficiency phenotype in heterozygous mice carrying an insulin‐like growth factor II gene disrupted by targeting. Nature 345: 78–80, 1990.
 63. DeChiara, T. M., E. J. Robertson, and A. Efstratiadis. Parental imprinting of the mouse insulin‐like growth factor II gene. Cell 64: 849–859, 1991.
 64. Delafontaine, P. Insulin‐like growth factor I and its binding proteins in the cardiovascular system. Cardiovasc. Res. 30: 825–834, 1995.
 65. Delany, A. M., and E. Canalis. Transcriptional repression of insulin‐like growth factor I by glucocorticoids in rat bone cells. Endocrinology 136: 4776–4781, 1995.
 66. Descombes, P., and U. Schibler. A liver‐enriched transcriptional activator protein, LAP, and a transcriptional inhibitory protein, LIP, are translated from the same mRNA. Cell 67: 569–579, 1991.
 67. Doglio, A., C. Dani, G. Fredrikson, P. Grimaldi, and G. Ailhaud. Acute regulation of insulin‐like growth factor‐I gene expression by growth hormone during adipose cell differentiation. EMBO J. 6: 4011–4016, 1987.
 68. Drummond, I. A., S. L. Madden, P. Rohwer‐Nutter, G. I. Bell, and V. P. Sukhatme. Repression of the insulin‐like growth factor II gene by the Wilms tumor suppressor WT1. Science 257: 674–678, 1992.
 69. Drummond, I. A., H. D. Rupprecht, P. Rohwer‐Nutter, J. M. Lopez‐Guisa, S. L. R. Madden, and V. P. Sukhatme. DNA recognition by splicing variants of the Wilms' tumor suppressor, WT1. Mol. Cell. Biol. 14: 3800–3809, 1994.
 70. Duguay, S. J., S. J. Chan, T. P. Mommsen, and D. F. Steiner. Divergence of insulin‐like growth factors I and II in the elasmobranch, Squalus acanthias. FEBS Lett. 371: 69–72, 1995.
 71. Duguay, S. J., J. Lai‐Zhang, and D. F. Steiner. Mutational analysis of the insulin‐like growth factor I prohormone processing site. J. Biol. Chem. 270: 17566–17574, 1995.
 72. Duguay, S. J., W. M. Milewski, B. D. Young, K. Nakayama, and D. F. Steiner. Processing of wild‐type and mutant proinsulin‐like growth factor‐IA by subtilisin‐related proprotein convertases. J. Biol. Chem. 272: 6663–6670, 1997.
 73. Dull, T. J., A. Gray, J. S. Hayflick, and A. Ullrich. Insulin‐like growth factor II precursor gene organization in relation to insulin gene family. Nature 310: 777–781, 1984.
 74. Efstratiadis, A. Parental imprinting of autosomal mammalian genes. Curr. Opin. Genet. Dev. 4: 265–280, 1994.
 75. Ekstrom, T. J., H. Cui, X. Li, and R. Ohlsson. Promoter‐specific IGF2 imprinting status and its plasticity during human liver development. Development 121: 309–316, 1995.
 76. Ekstrom, T. J., H. Cui, A. Nystrom, E. M. Rutanen, and R. Ohlsson. Monoallelic expression of IGF2 at the human fetal/maternal boundary. Mol. Reprod. Dev. 41: 177–183, 1995.
 77. El‐Badry, O. M., J. A. Romanus, L. J. Helman, M. J. Cooper, M. M. Rechler, and M. A. Israel. Autonomous growth of a human neuroblastoma cell line is mediated by insulin‐like growth factor II. J. Clin. Invest. 84: 829–839, 1989.
 78. Emler, C. A., and D. S. Schalch. Nutritionally‐induced changes in hepatic insulin‐like growth factor I (IGF‐I) gene expression in rats. Endocrinology 120: 832–834, 1987.
 79. Eversole‐Cire, P., A. C. Ferguson‐Smith, H. Sasaki, et al. Activation of an imprinted Igf 2 gene in mouse somatic cell cultures. Mol. Cell. Biol. 13: 4928–4938, 1993.
 80. Feil, R., J. Walter, N. D. Allen, and W. Reik, Developmental control of allelic methylation in the imprinted mouse Igf2 and H19 genes. Development 120: 2933–2943, 1994.
 81. Ferguson‐Smith, A. C., B. M. Cattanach, S. C. Barton, C. V. Beechey, and M. A. Surani. Embryological and molecular investigations of parental imprinting on mouse chromosome 7 [see comments]. Nature 351: 667–670, 1991.
 82. Ferguson‐Smith, A. C., H. Sasaki, B. M. Cattanach, and M. A. Surani. Parental‐origin‐specific epigenetic modification of the mouse H19 gene. Nature 362: 751–755, 1993.
 83. Fotsis, T., C. Murphy, and F. Gannon. Nucleotide sequence of the bovine insulin‐like growth factor 1 (IGF‐1) and its IGF‐1A precursor. Nucleic Acids Res. 18: 676, 1990.
 84. Foyt, H. L., F. Lanau, M. Woloschak, D. LeRoith, and C. T. Roberts, Jr. Effect of growth hormone on levels of differentially processed insulin‐like growth factor I mRNAs in total and pol‐ysomal mRNA populations. Mol. Endocrinol. 6: 1881–1888, 1992.
 85. Foyt, H. L., D. LeRoith, and C. T. Roberts, Jr. Differential association of insulin‐like growth factor I mRNA variants with polysomes in vivo. J. Biol. Chem. 266: 7300–7305, 1991.
 86. Frunzio, R., L. Chiariotti, A. L. Brown, D. E. Graham, M. M. Rechler, and C. B. Bruni. Structure and expression of the rat insulin‐like growth factor II (rIGF‐II) gene. rIGF‐II RNAs are transcribed from two promoters. J. Biol. Chem. 261: 17138–17149, 1986.
 87. Garcia‐Estrada, J., L. M. Garcia‐Segura, and I. Torres‐Aleman. Expression of insulin‐like growth factor I by astrocytes in response to injury. Brain Res. 592: 343–347, 1992.
 88. Giannoukakis, N., C. Deal, J. Paquette, C. G. Goodyer, and C. Polychronakos. Parental genomic imprinting of the human IGF2 gene. Nat. Genet. 4: 98–101, 1993.
 89. Gil, A., P. A. Sharp, S. F. Jamison, and M. A. Garcia‐Blanco. Characterization of cDNAs encoding the polypyrimidine tract‐binding protein. Genes Dev. 5: 1224–1236, 1991.
 90. Glaser, A., H. Luthman, I. Stern, and R. Ohlsson. Spatial distribution of active genes implicated in the regulation of insulinlike growth factor stimulatory loops in human decidual and placental tissue of first‐trimester pregnancy. Mol. Reprod. Dev. 33: 7–15, 1992.
 91. Gloudemans, T., I. Prinsen, J. A. Van Unnik, C.J. Lips, and W. Den Otter. Insulin‐like growth factor gene expression in human smooth muscle tumors. Cancer Res. 50: 6689–6695, 1990.
 92. Gluckman, P., N. Klempt, J. Guan, et al. A role for IGF‐1 in the rescue of CNS neurons following hypoxic‐ischemic injury. Biochem. Biophys. Res. Commun. 182: 593–599, 1992.
 93. Gowan, L. K., B. Hampton, D. J. Hill, R. J. Schlueter, and J. F. Perdue. Purification and characterization of a unique high molecular weight form of insulin‐like growth factor II. Endocrinology 121: 449–458, 1987.
 94. Graham, D. E., M. M. Rechler, A. L. Brown, et al. Coordinate developmental regulation of high and low molecular weight mRNAs for rat insulin‐like growth factor II. Proc. Natl. Acad. Sci. USA 83: 4519–4523, 1986.
 95. Grant, M. B., R. N. Mames, C. Fitzgerald, E. A. Ellis, M. Aboufriekha, and J. Guy. Insulin‐like growth factor I acts as an angiogenic agent in rabbit cornea and retina: comparative studies with basic fibroblast growth factor. Diabetologia 36: 282–291, 1993.
 96. Gray, A., A. W. Tam, T. J. Dull, et al. Tissue‐specific and developmentally regulated transcription of the insulin‐like growth factor 2 gene. DNA 6: 283–295, 1987.
 97. Gronowski, A. M., C. Le Stunff, and P. Rotwein. Acute nuclear actions of growth hormone (GH): cycloheximide inhibits inducible activator protein‐1 activity, but does not block GH‐regulated signal transducer and activator of transcription activation or gene expression. Endocrinology 137: 55–64, 1996.
 98. Gronowski, A. M., and P. Rotwein. Rapid changes in nuclear protein tyrosine phosphorylation after growth hormone treatment in vivo. Identification of phosphorylated mitogen‐activated protein kinase and STAT91. J. Biol. Chem. 269: 7874–7878, 1994.
 99. Gronowski, A. M., and P. Rotwein. Rapid changes in gene expression after in vivo growth hormone treatment. Endocrinology 136: 4741–4748, 1995.
 100. Gronowski, A. M., Z. Zhong, Z. Wen, M. J. Thomas, J. E. Darnell, Jr., and P. Rotwein. In vivo growth hormone treatment rapidly stimulates the tyrosine phosphorylation and activation of Stat3. Mol. Endocrinol. 9: 171–177, 1995.
 101. Hadsell, D. L., N. M. Greenberg, J. M. Fligger, C. R. Baumrucker, and J. M. Rosen. Targeted expression of des human insulin‐like growth factor I in transgenic mice influences mammary gland development and IGF‐binding protein expression. Endocrinology 137: 321–330, 1996.
 102. Hall, L. J., Y. Kajimoto, D. Bichell, et al. Functional analysis of the rat insulin‐like growth factor I gene and identification of an IGF‐I gene promoter. DNA Cell Biol. 11: 301–313, 1992.
 103. Han, V. K., A. J. D'Ercole, and P. K. Lund. Cellular localization of somatomedin (insulin‐like growth factor) messenger RNA in the human fetus. Science 236: 193–197, 1987.
 104. Han, V. K., P. K. Lund, D. C. Lee, and A. J. D'Ercole. Expression of somatomedin/insulin‐like growth factor messenger ribonucleic acids in the human fetus: identification, characterization, and tissue distribution. J. Clin. Endocrinol. Metab. 66: 422–429, 1988.
 105. Harp, J. B., S. Goldstein, and L. S. Phillips. Nutrition and somatomedin. XXIII. Molecular regulation of IGF‐I by amino acid availability in cultured hepatocytes. Diabetes 40: 95–101, 1991.
 106. Hayden, J. M., N. W. Marten, E. J. Burke, and D. S. Straus. The effect of fasting on insulin‐like growth factor‐I nuclear transcript abundance in rat liver. Endocrinology 134: 760–768, 1994.
 107. Heim, M. H. The Jak‐STAT pathway: specific signal transduction from the cell membrane to the nucleus. Eur. J. Clin. Invest. 26: 1–12, 1996.
 108. Hepler, J. E., J. J. van Wyk, and P. K. Lund. Different half‐lives of insulin‐like growth factor I mRNAs that differ in length of 3′ untranslated sequence. Endocrinology 127: 1550–1552, 1990.
 109. Hernandez, E. R. Regulation of the genes for insulin‐like growth factor (IGF) I and II and their receptors by steroids and gonadotropins in the ovary. J. Steroid Biochem. Mol. Biol. 53: 219–221, 1995.
 110. Holthuizen, P., F. M. van der Lee, K. Ikejiri, M. Yamamoto, and J. S. Sussenbach. Identification and initial characterization of a fourth leader exon and promoter of the human IGF‐II gene. Biochim. Biophys. Acta 1087: 341–343, 1990.
 111. Holthuizen, P. E., C. B. Cleutjens, G. J. Veenstra, F. M. van der Lee, and J. S. Sussenbach. Differential expression of the human, mouse and rat IGF‐II genes. Regul. Pept. 48: 77–89, 1993.
 112. Hoyt, E. C. A study of multiple signal peptides of insulin‐like growth factor 1. Master's Thesis. Department of Physiology, University of North Carolina at Chapel Hill, 1997.
 113. Hoyt, E. C., J. E. Hepler, J. J. van Wyk, and P. K. Lund. Structural characterization of exon 6 of the rat IGF‐I gene. DNA Cell. Biol. 11: 433–441, 1992.
 114. Hoyt, E. C., J. J. van Wyk, and P. K. Lund. Tissue and development specific regulation of a complex family of rat insulinlike growth factor I messenger ribonucleic acids. Mol. Endocrinol. 2: 1077–1086, 1988.
 115. Hu, J. F., T. H. Vu, and A. R. Hoffman. Differential biallelic activation of three insulin‐like growth factor II promoters in the mouse central nervous system. Mol. Endocrinol. 9: 628–636, 1995.
 116. Hu, J. F., T. H. Vu, and A. R. Hoffman. Promoter‐specific modulation of insulin‐like growth factor II genomic imprinting by inhibitors of DNA methylation. J. Biol. Chem. 271: 18253–18262, 1996.
 117. Huang, S., P.M. Thule, and L. S. Phillips. Identification of novel promoter and repressor elements in the 5′‐flanking regions of the rat insulin‐like growth factor‐I gene. Biochem. Biophys. Res. Commun. 206: 279–286, 1995.
 118. Hudgins, W. R., B. Hampton, W. H. Burgess, and J. F. Perdue. Evidence for O‐glycosylation of insulin‐like growth factor‐II precursors. In: Modern Concepts of Insulin‐Like Growth Factors, edited by E. M. Spencer. New York: Elsevier Press, 1991, p. 253–263.
 119. Hylka, V. W., S. B. Kent, and D. S. Straus. E‐domain peptide of rat proinsulin‐like growth factor‐II: validation of a radioimmunoassay and measurement in culture medium and rat serum. Endocrinology 120: 2050–2058, 1987.
 120. Hynes, M. A., P.J. Brooks, J. J. van Wyk, and P. K. Lund. Insulin‐like growth factor II messenger ribonucleic acids are synthesized in the choroid plexus of the rat brain. Mol. Endocrinol. 2: 47–54, 1988.
 121. Hynes, M. A., J. J. van Wyk, P. J. Brooks, A. J. D'Ercole, M. Jansen, and P. K. Lund. Growth hormone dependence of somatomedin‐C/insulin‐like growth factor‐I and insulin‐like growth factor‐II messenger ribonucleic acids. Mol. Endocrinol. 1: 233–242, 1987.
 122. Ikejiri, K., M. Furuichi, T. Ueno, T. Matsuguchi, K. Takahashi, and H. Endo. The presence and active transcription of three independent leader exons in the mouse insulin‐like growth factor II gene. Biochim. Biophys. Acta 1089: 77–82, 1991.
 123. Ikejiri, K., T. Ueno, T. Matsuguchi, K. Takahashi, H. Endo, and M. Yamamoto. The primary structure of the rat insulinlike growth factor II gene region. Biochim. Biophys. Acta 1049: 350–353, 1990.
 124. Ishii, D. N., G. W. Glazner, and S. F. Pu. Role of insulin‐like growth factors in peripheral nerve regeneration. Pharmacol. Ther. 62: 125–144, 1994.
 125. Jansen, E., P. H Steenbergh, D. LeRoith, C. T. Roberts, Jr., and J. S. Sussenbach. Identification of multiple transcription start sites in the human insulin‐like growth factor‐I gene. Mol. Cell. Endocrinol. 78: 115–125, 1991.
 126. Jansen, E., P. H. Steenbergh, F. M. van Schaik, and J. S. Sussenbach. The human IGF‐I gene contains two cell type‐specifically regulated promoters. Biochem. Biophys. Res. Commun. 187: 1219–1226, 1992.
 127. Jansen, M., F. M. van Schaik, A. T. Ricker, et al. Sequence of cDNA encoding human insulin‐like growth factor I precursor. Nature 306: 609–611, 1983.
 128. Jansen, M., F. M. van Schaik, H. van Tol, J. L. Van den Brande, and J. S. Sussenbach. Nucleotide sequences of cDNAs encoding precursors of human insulin‐like growth factor II (IGF‐II) and an IGF‐II variant. FEBS Lett. 179: 243–246, 1985.
 129. Jones, J. I., M. E. Doerr, and D. R. Clemmons. Cell migration: interactions among integrins, IGFs and IGFBPs. Prog. Growth Factor Res. 6: 319–327, 1995.
 130. Junien, C. Beckwith‐Wiedemann syndrome, tumourigenesis and imprinting [published erratum appears in Curr. Opin. Genet. Dev. 2: 651, 1992]. [Review] [59 refs]. Curr. Opin. Genet. Dev. 2: 431–438, 1992.
 131. Kachra, Z., I. Barash, C. Yannopoulos, M.N. Khan, H.J. Guyda, and B. I. Posner. The differential regulation by glucagon and growth hormone of insulin‐like growth factor (IGF)‐I and IGF binding proteins in cultured rat hepatocytes. Endocrinology 128: 1723–1730, 1991.
 132. Kachra, Z., C. R. Yang, and B. I. Posner. The augmentation of insulin‐like growth factor‐I messenger ribonucleic acid in cultured rat hepatocytes: activation of protein kinase‐A and‐C is necessary, but not sufficient. Endocrinology 134: 702–708, 1994.
 133. Kaestner, K. H., H. Hiemisch, B. Luckow, and G. Schutz. The HNF‐3 gene family of transcription factors in mice: gene structure, cDNA sequence, and mRNA distribution. Genomics 20: 377–385, 1994.
 134. Kajimoto, Y., and P. Rotwein. Structure and expression of a chicken insulin‐like growth factor I precursor. Mol. Endocrinol. 3: 1907–1913, 1989.
 135. Kajimoto, Y., and P. Rotwein. Evolution of insulin‐like growth factor I (IGF‐I): structure and expression of an IGF‐I precursor from Xenopus laevis. Mol. Endocrinol. 4: 217–226, 1990.
 136. Kajimoto, Y., and P. Rotwein. Structure of the chicken insulinlike growth factor I gene reveals conserved promoter elements. J. Biol. Chem. 266: 9724–9731, 1991.
 137. Kalscheuer, V. M., E. C. Mariman, M. T. Schepens, H. Rehder, and H. H. Ropers. The insulin‐like growth factor type‐2 receptor gene is imprinted in the mouse but not in humans. Nat. Gene. 5: 74–78, 1993.
 138. Kamai, Y., S. Mikawa, K. Endo, H. Sakai, and T. Komano. Regulation of insulin‐like growth factor‐I expression in mouse preadipocyte Ob1771 cells. J. Biol. Chem. 271: 9883–9886, 1996.
 139. Kavsan, V. M., A. P. Koval, V. A. Grebenjuk, et al. Structure of the chum salmon insulin‐like growth factor I gene. DNA Cell Biol. 12: 729–737, 1993.
 140. Kikuchi, K., D. P. Bichell, and P. Rotwein. Chromatin changes accompany the developmental activation of insulin‐like growth factor I gene transcription. J. Biol. Chem. 267: 21505–21511, 1992.
 141. Kim, S. W., R. Lajara, and P. Rotwein. Structure and function of a human insulin‐like growth factor‐I gene promoter. Mol. Endocrinol. 5: 1964–1972, 1991.
 142. Kirstein, M., C. Aston, R. Hintz, and H. Vlassara. Receptor‐specific induction of insulin‐like growth factor I in human monocytes by advanced glycosylation end product‐modified proteins. J. Clin. Invest. 90: 439–446, 1992.
 143. Klein, S., D. R. Morrice, H. Sang, L. B. Crittenden, and D. W. Burt. Genetic and physical mapping of the chicken IGF1 gene to chromosome 1 and conservation of synteny with other vertebrate genomes. J. Hered. 87: 10–14, 1996.
 144. Komoly, S., L. D. Hudson, H. D. Webster, and C. A Bondy. Insulin‐like growth factor I gene expression is induced in astrocytes during experimental demyelination. Proc. Natl. Acad. Sci. USA 89: 1894–1898, 1992.
 145. Kovacs, E. J., and L. A. DiPietro. Fibrogenic cytokines and connective tissue production. FASEB J. 8: 854–861, 1994.
 146. Koval, A., V. Kulik, S. Duguay, et al. Characterization of a salmon insulin‐like growth factor I promoter. DNA Cell Biol. 13: 1057–1062, 1994.
 147. Kozak, M. Regulation of translation in eukaryotic systems. Annu. Rev. Cell Biol. 8: 197–225, 1992.
 148. Kulik, V. P., V. M. Kavsan, F. M. van Schaik, L. A. Nolten, and P. H. Steenbergh. The promoter of the salmon insulin‐like growth factor I gene is activated by hepatocyte nuclear factor 1. J. Biol. Chem. 270: 1068–1073, 1995.
 149. Lahm, H., P. Amstad, J. Wyniger, et al. Blockade of the insulinlike growth‐factor‐I receptor inhibits growth of human colorectal cancer cells: evidence of a functional IGF‐II‐mediated autocrine loop. Int. J. Cancer 58: 452–459, 1994.
 150. Lai, E., and J. E. Darnell, Jr. Transcriptional control in hepat‐ocytes: a window on development. Trends Biochem. Sci. 16: 427–430, 1991.
 151. Lake, F. R., P. W. Noble, P. M. Henson, and D. W. Riches. Functional switching of macrophage responses to tumor necrosis factor‐alpha (TNF alpha) by interferons. Implications for the pleiotropic activities of TNF alpha. J. Clin. Invest. 93: 1661–1669, 1994.
 152. Latham, K. E., A. S. Doherty, C. D. Scott, and R. M. Schultz. Igf2r and Igf2 gene expression in androgenetic, gynogenetic, and parthenogenetic preimplantation mouse embryos: absence of regulation by genomic imprinting. Genes Dev. 8: 290–299, 1994.
 153. Le Stunff, C., M. J. Thomas, and P. Rotwein, Rapid activation of rat insulin‐like growth factor‐I gene transcription by growth hormone reveals no changes in deoxyribonucleic acid‐protein interactions within the second promoter. Endocrinology 136: 2230–2237, 1995.
 154. Lee, J. E., U. Tantravahi, A. L. Boyle, and A. Efstratiadis. Parental imprinting of an Igf‐2 transgene. Mol. Reprod. Dev. 35: 382–390, 1993.
 155. Lee, W. H., G. M. Wang, L. B. Seaman, and S. J. Vannucci. Coordinate IGF‐I and IGFBP5 gene expression in perinatal rat brain after hypoxiaischemia. J. Cereb. Blood Flow Metab. 16: 227–236, 1996.
 156. Leighton, P. A., R. S. Ingram, J. Eggenschwiler, A. Efstratiadis, and S. M. Tilghman. Disruption of imprinting caused by deletion of the H19 gene region in mice. Nature 375: 34–39, 1995.
 157. Leighton, P. A., J. R. Saam, R. S. Ingram, C. L. Stewart, and S. M. Tilghman. An enhancer deletion affects both H19 and Igf2 expression. Genes Dev. 9: 2079–2089, 1995.
 158. Levinovitz, A. and G. Norstedt. Developmental and steroid hormonal regulation of insulin‐like growth factor II expression. Mol. Endocrinol. 3: 797–804, 1989.
 159. Li, E., C. Beard, and R. Jaenisch. Role for DNA methylation in genomic imprinting. Nature 366: 362–365, 1993.
 160. Li, X., H. Cui, B. Sandstedt, H. Nordlinder, E. Larsson, and T. J. Ekstrom. Expression levels of the insulin‐like growth factor‐II gene (IGF2) in the human liver: developmental relationships of the four promoters. J. Endocrinol. 149: 117–124, 1996.
 161. Liu, J. P., J. Baker, A. S. Perkins, E. J. Robertson, and A. Efstratiadis. Mice carrying null mutations of the genes encoding insulin‐like growth factor I (Igf‐1) and type 1 IGF receptor (Igflr). Cell 75: 59–72, 1993.
 162. Liu, X., D. Yao, and H. D. Webster. Insulin‐like growth factor I treatment reduces clinical deficits and lesion severity in acute demyelinating experimental autoimmune encephalomyelitis. Multiple Sclerosis 1: 2–9, 1995.
 163. Lowe, Jr., W. L., M. Adamo, H. Werner, C. T. Roberts, Jr., and D. LeRoith. Regulation by fasting of rat insulin‐like growth factor I and its receptor. Effects on gene expression and binding. J. Clin. Invest. 84: 619–626, 1989.
 164. Lowe, Jr., W. L., S. R. Lasky, D. LeRoith, and C. T. Roberts, Jr. Distribution and regulation of rat insulin‐like growth factor I messenger ribonucleic acids encoding alternative carboxyterminal E‐peptides: evidence for differential processing and regulation in liver. Mol. Endocrinol. 2: 528–535, 1988.
 165. Lowe, Jr., W. L., C. T. Roberts, Jr., S. R. Lasky, and D. LeRoith. Differential expression of alternative 5′untranslated regions in mRNAs encoding rat insulin‐like growth factor I. Proc. Natl. Acad. Sci. USA 84: 8946–8950, 1987.
 166. Lowe, Jr., W. L., and R. M. Teasdale. Characterization of a rat insulin‐like growth factor I gene promoter. Biochem. Biopbys. Res. Commun. 189: 972–978, 1992.
 167. Lund, P. K. Transcriptional and post‐transcriptional regulation of protein synthesis. Growth Regul. 4 Suppl 1: 1–5, 1994.
 168. Lund, P. K. Insulin‐like growth factors. In: Gut Peptides: Biochemistry and Physiology, edited by G. Dockray, and J. H. Walsh. New York: Raven Press, 1994, p. 587–613.
 169. Lund, P. K. Insulin‐like growth factor I: molecular biology and relevance to tissue‐specific expression and action. Recent Prog. Horm. Res. 49: 125–148, 1994.
 170. Lund, P. K., E. C. Hoyt, and J. J. van Wyk. The size heterogeneity of rat insulin‐like growth factor‐I mRNAs is due primarily to differences in the length of 3′‐untranslated sequence. Mol. Endocrinol. 3: 2054–2061, 1989.
 171. Lund, P. K., B. M. Moats‐Staats, M. A. Hynes, et al. Somatomedin‐C/insulin‐like growth factor‐I and insulin‐like growth factor‐II mRNAs in rat fetal and adult tissues. J. Biol. Chem. 261: 14539–14544, 1986.
 172. Lund, P. K., and E. M. Zimmermann. Insulin‐like growth factors and inflammatory bowel disease. Baillieres Clin. Gastroenterol. 10: 83–96, 1996.
 173. Mathews, L. S., R. E. Hammer, R. L. Brinster, and R. D. Palmiter. Expression of insulin‐like growth factor I in transgenic mice with elevated levels of growth hormone is correlated with growth. Endocrinology 123: 433–437, 1988.
 174. Mathews, L. S., G. Norstedt, and R. D. Palmiter. Regulation of insulin‐like growth factor I gene expression by growth hormone. Proc. Natl. Acad. Sci. USA 83: 9343–9347, 1986.
 175. Mavrothalassitis, G. J., D. K. Watson, and T. S. Papas. Molecular and functional characterization of the promoter of ETS2, the human c‐ets‐2 gene. Proc. Natl. Acad. Sci. USA 87: 1047–1051, 1990.
 176. McBratney, S., C. Y. Chen, and P. Sarnow. Internal initiation of translation. Curr. Opin. Cell Biol. 5: 961–965, 1993.
 177. McCarthy, T. L., J. Changhua, H. Shu, S. Casinghino, K. Crotherst, P. Rotwein, and M. Centrella. 17b‐estradiol potently suppresses cAMP‐induced insulin‐like growth factor‐I gene activation in primary rat osteoblast cultures. J. Biol. Chem. 272: 18132–18139, 1997.
 178. McCarthy, T. L., M. J. Thomas, M. Centrella, and P. Rotwein. Regulation of insulin‐like growth factor I transcription by cyclic adenosine 3′,5′‐monophosphate (cAMP) in fetal rat bone cells through an element within exon 1: protein kinase A‐dependent control without a consensus AMP response element. Endocrinology 136: 3901–3908, 1995.
 179. Meinsma, D., P. E. Holthuizen, J. L. Van den Brande, and J. S. Sussenbach. Specific endonucleolytic cleavage of IGF‐II m‐RNAs. Biochem. Biophys. Res. Commun. 179: 1509–1516, 1991.
 180. Meinsma, D., W. Scheper, P. E. Holthuizen, J. L. Van den Brande, and J. S. Sussenbach. Site‐specific cleavage of IGF‐II mRNAs requires sequence elements from two distinct regions of the IGF‐II gene. Nucleic Acids Res. 20: 5003–5009, 1992.
 181. Moore, T., and D. Haig. Genomic imprinting in mammalian development: a parental tug‐of‐war. Trends Genet. 7: 45–49, 1991.
 182. Moulton, T., T. Crenshaw, Y. Hao, et al. Epigenetic lesions at the H19 locus in Wilms' tumour patients. Nat. Genet. 7: 440–447, 1994.
 183. Muller, M., and G. Brem. Nucleotide sequence of porcine insulin‐like growth factor. 1.5′untranslated region, exons 1 and 2 and mRNA. Nucleic Acids Res. 18: 364, 1990.
 184. Murphy, L. J., and H. G. Friesen. Differential effects of estrogen and growth hormone on uterine and hepatic insulin‐like growth factor I gene expression in the ovariectomized hypophysectomized rat. Endocrinology 122: 325–332, 1988.
 185. Nagaoka, I., A. Someya, K. Iwabuchi, and T. Yamashita. Expression of insulin‐like growth factor‐IA and factor‐IB mRNA in human liver, hepatoma cells, macrophage‐like cells and fibroblasts. FEBS Letts. 280: 79–83, 1991.
 186. Nardone, G., M. Romano, A. Calabro, et al. Activation of fetal promoters of insulinlike growth factors II gene in hepatitis C virus‐related chronic hepatitis, cirrhosis, and hepatocellular carcinoma. Hepatology 23: 1304–1312, 1996.
 187. Nielsen, F. C., S. Gammeltoft, and J. Christiansen, Translational discrimination of mRNAs coding for human insulin‐like growth factor II. J. Biol. Chem. 265: 13431–13434, 1990.
 188. Nielsen, F. C., L. Ostergaard, J. Nielsen, and J. Christiansen. Growth‐dependent translation of IGF‐II mRNA by a rapamycin‐sensitive pathway. Nature 377: 358–362, 1995.
 189. Noble, P. W., F. R. Lake, P. M. Henson, and D. W. Riches. Hyaluronate activation of CD44 induces insulin‐like growth factor‐1 expression by a tumor necrosis factor‐alpha‐dependent mechanism in murine macrophages. J. Clin. Invest. 91: 2368–2377, 1993.
 190. Nolten, L. A., P. H. Steenbergh, and J. S. Sussenbach. Hepatocyte nuclear factor 1 alpha activates promoter 1 of the human insulin‐like growth factor I gene via two distinct binding sites. Mol. Endocrinol. 9: 1488–1499, 1995.
 191. Nolten, L. A., P. H. Steenbergh, and J. S. Sussenbach. The hepatocyte nuclear factor 3beta stimulates the transcription of the human insulin‐like growth factor I gene in a direct and indirect manner. J. Biol. Chem. 271: 31846–31854, 1996.
 192. Nolten, L. A., F. M. van Schaik, P. H. Steenbergh, and J. S. Sussenbach. Expression of the insulin‐like growth factor I gene is stimulated by the liver‐enriched transcription factors C/EBP alpha and LAP. Mol. Endocrinol. 8: 1636–1645, 1994.
 193. Norstedt, G., A. Levinovitz, C. Moller, L. C. Eriksson, and G. Andersson. Expression of insulin‐like growth factor I (IGF‐I) and IGF‐II mRNA during hepatic development, proliferation and carcinogenesis in the rat. Carcinogenesis 9: 209–213, 1988.
 194. O'Mahoney, J. V., and T. E. Adams. Nucleotide sequence of an ovine insulin‐like growth factor‐II cDNA. Nucleic Acids Res. 17: 5392, 1989.
 195. Ohlsson, R., and G. Franklin. Normal development and neoplasia: the imprinting connection. Int. J. Dev. Biol. 39: 869–876, 1995.
 196. Ohlsson, R., F. Hedborg, L. Holmgren, C. Walsh, and T. J. Ekstrom. Overlapping patterns of IGF2 and H19 expression during human development: biallelic IGF2 expression correlates with a lack of H19 expression. Development 120: 361–368, 1994.
 197. Ohlsson, R., A. Nystrom, S. Pfeifer‐Ohlsson, et al. IGF2 is parentally imprinted during human embryogenesis and in the Beckwith‐Wiedemann syndrome. Nat. Genet. 4: 94–97, 1993.
 198. Ohneda, K., M. H. Ulshen, C. R. Fuller, A. J. D'Ercole, and P. K. Lund. Enhanced growth of small bowel in transgenic mice expressing human insulin‐like growth factor I. Gastroenterology 112: 444–454, 1997.
 199. Pao, C. I., K. W. Lin, J. Zhu, G. Wu, P. K. Farmer, and L. S. Phillips. In vitro transcription of the rat insulin‐like growth factor‐I gene. J. Biol. Chem. 271: 8667–8674, 1996.
 200. Pedone, P. V., M. P. Cosma, P. Ungaro, V. Colantuoni, C. B. Bruni, and R. Zarrilli. Parental imprinting of rat insulin‐like growth factor II gene promoters is coordinately regulated. J. Biol. Chem. 269: 23970–23975, 1994.
 201. Pell, J. M., J. C. Saunders, and R. S. Gilmour. Differential regulation of transcription initiation from insulin‐like growth factor‐I (IGF‐I) leader exons and of tissue IGF‐I expression in response to changed growth hormone and nutritional status in sheep. Endocrinology 132: 1797–1807, 1993.
 202. Perfetti, R., L. A. Scott, and A. R. Shuldiner. The two nonallelic insulin‐like growth factor‐I genes in Xenopus laevis are differentially regulated during development. Endocrinology 135: 2037–2044, 1994.
 203. Poli, V., F. P. Mancini, and R. Cortese. IL‐6DBP, a nuclear protein involved in interleukin‐6 signal transduction, defines a new family of leucine zipper proteins related to C/EBP. Cell 63: 643–653, 1990.
 204. Powell, D. R., P. D. Lee, D. Chang, F. Liu, and R. L. Hintz, R. L. Antiserum. developed for the E peptide region of insulinlike growth factor IA prohormone recognizes a serum protein by both immunoblot and radioimmunoassay. J. Clin. Endocrinol. Metab. 65: 868–875, 1987.
 205. Powell‐Braxton, L., P. Hollingshead, C. Warburton, et al. IGF‐I is required for normal embryonic growth in mice. Genes Dev. 7: 2609–2617, 1993.
 206. Ranke, M. B., W. F. Blum, and J. R. Bierich. Clinical relevance of serum measurements of insulin‐like growth factors and somatomedin binding proteins. Acta Paediatr. Scand. Suppl. 347: 114–126, 1988.
 207. Rappolee, D. A., D. Mark, M. J. Banda, and Z. Werb. Wound macrophages express TGF‐alpha and other growth factors in vivo: analysis by mRNA phenotyping. Science 241: 708–712, 1988.
 208. Rechler, M. M., C. B. Bruni, H. J. Whitfield, et al. Characterization of the biosynthetic precursor for the rat insulin‐like growth factor II by biosynthetic labeling, radiosequencing, and nucleotide sequence analysis, of a cDNA clone. Cancer Cells: Growth Factors and Transformation 3: 131–138, 1985.
 209. Rechler, M. M., and S. P. Nissley. Insulin‐Like Growth Factors. In: Peptide Growth Factors and Their Receptors, edited by M. B. Sporn, and A. B. Roberts. New York: Springer‐Verlag, 1990, p. 263–267.
 210. Reeve, A. E., M. R. Eccles, R. J. Wilkins, G. I. Bell, and L. J. Millow. Expression of insulin‐like growth factor‐II transcripts in Wilms' tumour. Nature 317: 258–260, 1985.
 211. Reiss, K., W. Cheng, A. Ferber, et al. Overexpression of insulin‐like growth factor‐1 in the heart is coupled with myocyte proliferation in transgenic mice. Proc. Natl. Acad. Sci. USA 93: 8630–8635, 1996.
 212. Rifkin, D. B., and D. Moscatelli, Recent developments in the cell biology of basic fibroblast growth factor. J. Cell. Biol. 109: 1–6, 1989.
 213. Roberts, C. T., Jr., S. R. Lasky, W. L. Lowe, Jr., W. T. Seaman, and D. LeRoith. Molecular cloning of rat insulin‐like growth factor I complementary deoxyribonucleic acids: differential messenger ribonucleic acid processing and regulation by growth hormone in extrahepatic tissues. Mol. Endocrinol. 1: 243–248, 1987.
 214. Rodenburg, R. J., P. E. Holthuizen, and J. S. Sussenbach. A functional Sp1 binding site is essential for the activity of the adult liver‐specific human insulin‐like growth factor II promoter. Mol. Endocrinol. 11: 237–250, 1997.
 215. Rodenburg, R. J., W. Teertstra, P. E. Holthuizen, and J. S. Sussenbach. Postnatal liver‐specific expression of human insulinlike growth factor‐II is highly stimulated by the transcriptional activators liver‐enriched activating protein and CCAAT/en‐hancer binding protein‐alpha. Mol. Endocrinol. 9: 424–434, 1995.
 216. Rogler, C. E., D. Yang, L. Rossetti, et al. Altered body composition and increased frequency of diverse malignancies in insulin‐like growth factor‐II transgenic mice. J. Biol. Chem. 269: 13779–13784, 1994.
 217. Rom, W. N., P. Basset, G. A. Fells, T. Nukiwa, B. C. Trapnell, and R. G. Crysal. Alveolar macrophages release an insulin‐like growth factor I‐type molecule. J. Clin. Invest. 82: 1685–1693, 1988.
 218. Romanus, J. A., Y. W. Yang, S. O. Adams, A. N. Sofair, L. Y. Tseng, and S. P. Nissley. Synthesis of insulin‐like growth factor II (IGF‐II) in fetal rat tissues: translation of IGF‐II ribonucleic acid and processing of pre‐pro‐IGF‐II. Endocrinology 122: 709–716, 1988.
 219. Ross, J. mRNA stability in mammalian cells. Microbiol. Rev. 59: 423–450, 1995.
 220. Rotwein, P. Two insulin‐like growth factor I messenger RNAs are expressed in human liver. Proc. Natl. Acad. Sci. USA 83: 77–81, 1986.
 221. Rotwein, P., R. J. Folz, and J. I. Gordon. Biosynthesis of human insulin‐like growth factor I (IGF‐I). The primary translation product of IGF‐I mRNA contains an unusual 48‐amino acid signal peptide. J. Biol. Chem. 262: 11807–11812, 1987.
 222. Rotwein, P., A. M. Gronowski, and M.J. Thomas. Rapid nuclear actions of growth hormone. Horm. Res. 42: 170–175, 1994.
 223. Rotwein, P., and L. J. Hall, Evolution of insulin‐like growth factor II: characterization of the mouse IGF‐II gene and identification of two pseudoexons. DNA Cell Biol. 9: 725–735, 1990.
 224. Rotwein, P., K. M. Pollock, D. K. Didier, and G. G. Krivi. Organization and sequence of the human insulin‐like growth factor I gene. Alternative RNA processing produces two insulinlike growth factor I precursor peptides. J. Biol. Chem. 261: 4828–4832, 1986.
 225. Rotwein, P., K. M. Pollock, M. Watson, and J. D. Milbrandt. Insulin‐like growth factor gene expression during rat embryonic development. Endocrinology 121: 2141–2144, 1987.
 226. Sasaki, H., P. A. Jones, J. R. Chaillet, et al. Parental imprinting: potentially active chromatin of the repressed maternal allele of the mouse insulin‐like growth factor II (Igf2) gene. Genes Dev. 6: 1843–1856, 1992.
 227. Savendahl, L., L. E. Underwood, K. M. Haldeman, M. H. Ulshen, and P. K. Lund. Fasting prevents experimental murine colitis produced by dextran sulfate sodium and decreases interleukin‐1 beta and insulin‐like growth factor I messenger ribonucleic acid. Endocrinology 138: 734–740, 1997.
 228. Schalch, D. S., U. E. Heinrich, B. Draznin, C. J. Johnson, and L. L. Miller. Role of the liver in regulating somatomedin activity: hormonal effects on the synthesis and release of insulin‐like growth factor and its carrier protein by the isolated perfused rat liver. Endocrinology 104: 1143–1151, 1979.
 229. Scheper, W., P. E. Holthuizen, and J. S. Sussenbach. Growth‐condition‐dependent regulation of insulin‐like growth factor II mRNA stability. Biochem. J. 318: 195–201, 1996.
 230. Scheper, W., P. E. Holthuizen, and J. S. Sussenbach. The cis‐acting elements involved in endonucleolytic cleavage of the 3′UTR of human IGF‐II mRNAs bind a 50 kDa protein. Nucleic Acids Res. 24: 1000–1007, 1996.
 231. Scheper, W., D. Meinsma, P. E. Holthuizen, and J. S. Sussenbach. Long‐range RNA interaction of two sequence elements required for endonucleolytic cleavage of human insulin‐like growth factor II mRNAs. Mol. Cell. Biol. 15: 235–245, 1995.
 232. Schneid, H., P. E. Holthuizen, and J. S. Sussenbach, Differential promoter activation in two human insulin‐like growth factor‐II‐producing tumor cell lines. Endocrinology 132: 1145–1150, 1993.
 233. Schofield, P. N., and W. Engstrom. Insulin‐Like Growth Factors in Human Cancer. In: The Insulin‐Like Growth Factors: Structure and Biological Functions, edited by P. N. Schofield. Oxford: Oxford University Press, 1992, p. 240–257.
 234. Schultz, G. A., A. Hahnel, M. Arcellana‐Panlilio, et al. Expression of IGF ligand and receptor genes during preimplantation mammalian development. Mol. Reprod. Dev. 35: 414–420, 1993.
 235. Schwander, J. C., C. Hauri, J. Zapf, and E. R. Froesch. Synthesis and secretion of insulin‐like growth factor and its binding protein by the perfused rat liver: dependence on growth hormone status. Endocrinology 113: 297–305, 1983.
 236. Shimatsu, A., and P. Rotwein. Sequence of two rat insulin‐like growth factor I mRNAs differing within the 5′untranslated region. Nucleic Acids Res. 15: 7196, 1987.
 237. Shimatsu, A., and P. Rotwein. Mosaic evolution of the insulinlike growth factors. Organization, sequence, and expression of the rat insulin‐like growth factor I gene. J. Biol. Chem. 62: 7894–7900, 1987.
 238. Shinar, Y., and F. A. McMorris. Developing oligodendroglia express mRNA for insulin‐like growth factor‐I, a regulator of oligodendrocyte development. J. Neurosci. Res. 42: 516–527, 1995.
 239. Siegfried, J. M., P. G. Kasprzyk, A. M. Treston, J. L. Mulshine, and K. A. Quinn. A mitogenic peptide amide encoded within the E peptide domain of the insulin‐like growth factor IB prohormone. Proc. Natl. Acad. Sci. USA 89: 8107–8111, 1992.
 240. Simmons, J. G., J. J. van Wyk, E. C. Hoyt, and P. K. Lund. Multiple transcription start sites in the rat insulin‐like growth factor‐I gene give rise to IGF‐I mRNAs that encode different IGF‐I precursors and are processed differently in vitro. Growth Factors 9: 205–221, 1993.
 241. Smale, S. T., and D. Baltimore. The “initiator” as a transcription control element. Cell 57: 103–113, 1989.
 242. Soares, M. B., D. N. Ishii, and A. Efstratiadis. Developmental and tissue‐specific expression of a family of transcripts related to rat insulin‐like growth factor II mRNA. Nucleic Acids Res. 13: 1119–1134, 1985.
 243. Soares, M. B., A. Turken, D. Ishii, et al. Rat insulin‐like growth factor II gene. A single gene with two promoters expressing a multitranscript family. J. Mol. Biol. 192: 737–752, 1986.
 244. Squire, J., and R. Weksberg. Genomic imprinting in tumours. Semin. Cancer Biol. 7: 41–47, 1996.
 245. Steenbergh, P. H., A. M. Koonen‐Reemst, C. B. Cleutjens, and J. S. Sussenbach. Complete nucleotide sequence of the high molecular weight human IGF‐I mRNA. Biochem. Biophys. Res. Commun. 175: 507–514, 1991.
 246. Steenfos, H. H. Growth factors and wound healing. Scand. J. Plast. Reconstr. Surg. Hand Surg. 28: 95–105, 1994.
 247. Steenman, M. J., S. Rainier, C. J. Dobry, P. Grundy, I. L. Horon, and A. P. Feinberg. Loss of imprinting of IGF2 is linked to reduced expression and abnormal methylation of H19 in Wilms' tumour [published erratum appears in Nat. Genet. 8: 203, 1994]. Nat. Genet. 7: 433–439, 1994.
 248. Steller, M. A., C. H. Delgado, and Z. Zou. Insulin‐like growth factor II mediates epidermal growth factor‐induced mitogenesis in cervical cancer cells. Proc. Natl. Acad. Sci. USA 92: 11970–11974, 1995.
 249. Stempien, M. M., N. M. Fong, L. B. Rall, and G. I. Bell. Sequence of a placental cDNA encoding the mouse insulin‐like growth factor II precursor. DNA 5: 357–361, 1986.
 250. Stenvers, K., P. K. Lund, M. G. Baxter, and M. Gallagher. Two differentiating lesions of the hippocampus produce differential changes in IGF mRNA expression in rats. Neuroscience 1998. (Submitted)
 251. Stewart, C. E., and P. Rotwein, P. Growth. differentiation, and survival: multiple physiological functions for insulin‐like growth factors. Physiol. Rev. 76: 1005–1026, 1996.
 252. Straus, D. S., and C. D. Takemoto. Effect of fasting on insulinlike growth factor‐I (IGF‐I) and growth hormone receptor mRNA levels and IGF‐I gene transcription in rat liver. Mol. Endocrinol. 4: 91–100, 1990.
 253. Stylianopoulou, F., A. Efstratiadis, J. Herbert, and J. Pintar. Pattern of the insulin‐like growth factor II gene expression during rat embryogenesis. Development 103: 497–506, 1988.
 254. Stylianopoulou, F., J. Herbert, M. B. Soares, and A. Efstratiadis, Expression of the insulin‐like growth factor II gene in the choroid plexus and the leptomeninges of the adult rat central nervous system. Proc. Natl. Acad. Sci. USA 85: 141–145, 1988.
 255. Suh, D. Y., T. K. Hunt, and E. M. Spencer. Insulin‐like growth factor‐I reverses the impairment of wound healing induced by corticosteroids in rats. Endocrinology 131: 2399–2403, 1992.
 256. Surani, M. A., W. Reik, and N. D. Allen. Transgenes as molecular probes for genomic imprinting. Trends Genet. 4: 59–62, 1988.
 257. Sussenbach, J. S., R. J. Rodenburg, W. Scheper, and P. Holthuizen. Transcriptional and post‐transcriptional regulation of the human IGF‐II gene expression. Adv. Exp. Med. Biol. 343: 63–71, 1993.
 258. Sussenbach, J. S., R. J. T. Rodenburg, W. Scheper, and P. Holthuizen. Transcriptional and Post‐Transcriptional Regulation of the Human IGF‐II Gene Expression. In: Current Directions in Insulin‐Like Growth Factor Research, edited by D. LeRoith, and M. K. Raizada. New York: Plenum Press, 1994, p. 63.
 259. Szabo, P., and J. R. Mann. Expression and methylation of imprinted genes during in vitro differentiation of mouse parthenogenetic and androgenetic embryonic stem cell lines. Development 120: 1651–1660, 1994.
 260. Tavakkol, A., F. A. Simmen, and R. C. Simmen. Porcine insulin‐like growth factor‐I (pIGF‐I): complementary deoxyribonucleic acid cloning and uterine expression of messenger ribonucleic acid encoding evolutionarily conserved IGF‐I peptides. Mol. Endocrinol. 2: 674–681, 1988.
 261. Telford, N. A., A. Hogan, C. R. Franz, and G. A. Schultz. Expression of genes for insulin and insulin‐like growth factors and receptors in early postimplantation mouse embryos and embryonal carcinoma cells. Mol. Reprod. Dev. 27: 81–92, 1990.
 262. Thissen, J. P., J. M. Ketelslegers, and L. E. Underwood. Nutritional regulation of the insulin‐like growth factors. Endocr. Rev. 15: 80–101, 1994.
 263. Thissen, J. P., S. Triest, B. M. Moats‐Staats, L. E. Underwood, T. Mauerhoff, and J. M. Ketelslegers. Evidence that pretranslational and translational defects decrease serum insulin‐like growth factor‐I concentrations during dietary protein restriction. Endocrinology 129: 429–435, 1991.
 264. Thissen, J. P., and L. E. Underwood. Translational status of the insulin‐like growth factor‐I mRNAs in liver of protein‐restricted rats. J. Endocrinol. 132: 141–147, 1992.
 265. Thomas, M. J., K. Kikuchi, D. P. Bichell, and P. Rotwein. Rapid activation of rat insulin‐like growth factor‐I gene transcription by growth hormone reveals no alterations in deoxyribonucleic acid‐protein interactions within the major promoter. Endocrinology 135: 1584–1592, 1994.
 266. Thomas, M. J., K. Kikuchi, D. P. Bichell, and P. Rotwein. Characterization of deoxyribonucleic acid‐protein interactions at a growth hormone‐inducible nuclease hypersensitive site in the rat insulin‐like growth factor‐I gene. Endocrinology 136: 562–569, 1995.
 267. Tobin, G., D. Yee, N. Brunner, and P. Rotwein. A novel human insulin‐like growth factor I messenger RNA is expressed in normal and tumor cells. Mol. Endocrinol. 4: 1914–1920, 1990.
 268. Toilet, P., B. Enberg, and A. Mode. Growth hormone (GH) regulation of cytochrome P‐450IIC12, insulin‐like growth factor‐I (IGF‐I), and GH receptor messenger RNA expression in primary rat hepatocytes: a hormonal interplay with insulin, IGF‐I, and thyroid hormone. Mol. Endocrinol. 4: 1934–1942, 1990.
 269. Ueno, T., K. Takahashi, T. Matsuguchi, H. Endo, and M. Yamamoto. A new leader exon identified in the rat insulin‐like growth factor II gene. Biochem. Biophys. Res. Commun. 148: 344–349, 1987.
 270. Ueno, T., K. Takahashi, T. Matsuguchi, H. Endo, and M. Yamamoto. Transcriptional deviation of the rat insulin‐like growth factor II gene initiated at three alternative leader‐exons between neonatal tissues and ascites hepatomas. Biochim. Biophys. Acta 950: 411–419, 1988.
 271. Ueno, T., K. Takahashi, T. Matsuguchi, K. Ikejiri, H. Endo, and M. Yamamoto. Multiple polyadenylation sites in a large 3′‐most exon of the rat insulin‐like growth factor II gene. Biochim. Biophys. Acta 1009: 27–34, 1989.
 272. Underwood, L. E. Nutritional regulation of IGF‐I and IGFBPs. [Review] [42 refs]. J. Pediatr. Endocrinol. Metab. 9 (Suppl. 3): 303–312, 1996.
 273. Vallet, V., B. Antoine, P. Chafey, A. Vandewalle, and A. Kahn. Overproduction of a truncated hepatocyte nuclear factor 3 protein inhibits expression of liver‐specific genes in hepatoma cells. Mol. Cell. Biol. 15: 5453–5460, 1995.
 274. van Dijk, M. A., R. J. Rodenburg, P. Holthuizen, and J. S. Sussenbach. The liver‐specific promoter of the human insulin‐like growth factor II gene is activated by CCAAT/enhancer binding protein (C/EBP). Nucleic Acids Res. 20: 3099–3104, 1992.
 275. van Dijk, M. A., F. M. van Schaik, H. J. Bootsma, P. Holthuizen, and J. S. Sussenbach. Initial characterization of the four promoters of the human insulin‐like growth factor II gene. Mol. Cell. Endocrinol. 81: 81–94, 1991.
 276. Vikman, K., J. Isgaard, and S. Eden. Growth hormone regulation of insulin‐like growth factor‐I mRNA in rat adipose tissue and isolated rat adipocytes. J. Endocrinol. 131: 139–145, 1991.
 277. von Heijne, G. Analysis of the distrubion of charged residues in the N‐terminal region of signal sequences: implications for protein export in prokaryotic and eukaryotic cells. EMBO J. 3: 2315–2318, 1984.
 278. Vu, T. H., and A. R. Hoffman. Promoter‐specific imprinting of the human insulin‐like growth factor‐II gene. Nature 371: 714–717, 1994.
 279. Wang, J., W. Niu, Y. Niciforov, et al. Targeted overexpression of IGF‐I evokes distinct pattern of organ remodelling in smooth muscle cell tissue bed of transgenic mice. J. Clin. Invest. 100: 1425–1439, 1997.
 280. Ward, A., P. Bates, R. Fisher, L. Richardson, and C. F. Graham. Disproportionate growth in mice with Igf‐2 transgenes. Proc. Natl. Acad. Sci. USA 91: 10365–10369, 1994.
 281. Ward, A., J. A. Pooler, K. Miyagawa, A. Duarte, N. D. Hastie, and A. Caricasole. Repression of promoters for the mouse insulin‐like growth factor II‐encoding gene (Igf‐2) by products of the Wilms' tumour suppressor gene wt1. Gene 167: 239–243, 1995.
 282. Watanabe, S., and K. Arai. Roles of the JAK‐STAT system in signal transduction via cytokine receptors. Curr. Opin. Genet. Dev. 6: 587–596, 1996.
 283. Whitfield, H. J., C. B. Bruni, R. Frunzio, J. E. Terrell, S. P. Nissley, and M. M. Rechler. Isolation of a cDNA clone encoding rat insulin‐like growth factor‐II precursor. Nature 312: 277–280, 1984.
 284. Winesett, D. E., M. H. Ulshen, E. C. Hoyt, N. K. Mohapatra, C. R. Fuller, and P. K. Lund. Regulation and localization of the insulin‐like growth factor system in small bowel during altered nutrient status. Am. J. Physiol. 268 (Gastrointest. Liver Physiol. 31): G631–G640, 1995.
 285. Wong, E. A., S. M. Ohlsen, J. A. Godfredson, D. M. Dean, and J. E. Wheaton. Cloning of ovine insulin‐like growth factor‐I cDNAs: heterogeneity in the mRNA population. DNA 8: 649–657, 1989.
 286. Wood, T. L., M. Berelowitz, M. C. Gelato, et al. Hormonal regulation of rat hypothalamic neuropeptide mRNAs: effect of hypophysectomy and hormone replacement on growth‐hormone–releasing factor, somatostatin and the insulin‐like growth factors. Neuroendocrinology 53: 298–305, 1991.
 287. Wu, K. J., D. R. Wilson, C. Shih, and G. J. Darlington. The transcription factor HNF1 acts with C/EBP alpha to synergistically activate the human albumin promoter through a novel domain. J. Biol. Chem. 269: 1177–1182, 1994.
 288. Yamaguchi, F., T. Itano, O. Miyamoto, N. A. Janjua, T. Ohmoto, and K. Hosokawa. Increase of extracellular insulinlike growth factor I (IGF‐I) concentration following electrolyt‐ical lesion in rat hippocampus. Neurosci. Lett. 128: 273–276, 1991.
 289. Yang, H., M. L. Adamo, A. P. Koval, et al. Alternative leader sequences in insulin‐like growth factor I mRNAs modulate translational efficiency and encode multiple signal peptides. Mol. Endocrinol. 9: 1380–1395, 1995.
 290. Yang, Y. W., J. A. Romanus, T. Y. Liu, S. P. Nissley, and M. M. Rechler. Biosynthesis of rat insulin‐like growth factor II. I. Immunochemical demonstration of a approximately 20‐kilodalton biosynthetic precursor of rat insulin‐like growth factor II in metabolically labeled BRL‐3A rat liver cells. J. Biol. Chem. 260: 2570–2577, 1985.
 291. Yateman, M. E., D. C. Claffey, S. C. Cwyfan Hughes, V. J. Frost, J. A. Wass, and J. M. Holly. Cytokines modulate the sensitivity of human fibroblasts to stimulation with insulin‐like growth factor‐I (IGF‐I) by altering endogenous IGF‐binding protein production. J. Endocrinol. 137: 151–159, 1993.
 292. Ye, P., Y. Umayahara, D. Ritter, T. Bunting, H. Auman, P. Rotwein, and A. J. D'Ercole. Regulation of insulin‐like growth factor I (IGF‐I) gene expression in brain of transgenic mice expressing an IGF‐I‐luciferase fusion gene. Endocrinology 138: 5466–5475, 1997.
 293. Yoon, J. B., S. A. Berry, S. Seelig, and H. C. Towle. An inducible nuclear factor binds to a growth hormone‐regulated gene. J. Biol. Chem. 265: 19947–19954, 1990.
 294. Yun, K., A. E. Fidler, M. R. Eccles, and A. E. Reeve. Insulinlike growth factor II and WT1 transcript localization in human fetal kidney and Wilms' tumor. Cancer Res. 53: 5166–5171, 1993.
 295. Zeeh, J. M., N. Mohapatra, P. K. Lund, V. E. Eysselein, and J. A. McRoberts. Differential expression and localization of IGF‐I and IGF‐binding protein mRNA in inflamed rat colon. Gastroenterology 108: A948, 1995.
 296. Zhan, S., D. Shapiro, L. Zhang, S. Hirschfeld, J. Elassal, and L. J. Helman. Concordant loss of imprinting of the human insulin‐like growth factor II gene promoters in cancer. J. Biol. Chem. 270: 27983–27986, 1995.
 297. Zhang, L., F. Kashanchi, Q. Zhan, et al. Regulation of insulinlike growth factor II P3 promotor by p53: a potential mechanism for tumorigenesis. Cancer Res. 56: 1367–1373, 1996.
 298. Zhee, J. M., N. Mohapatra, P. K. Lund, V. E. Eysselein, and J. A. McRoberts. Differential expression and localization of IGF‐I and IGF binding proteins in inflamed rat colon. Gastroenterology 108: (Suppl.) A948, 1995
 299. Zimmermann, E. M., R. B. Sartor, R. D. McCall, M. Pardo, D. Bender, and P. K. Lund. Insulinlike growth factor I and interleukin 1 beta messenger RNA in a rat model of granulomatous enterocolitis and hepatitis. Gastroenterology 105: 399–409, 1993.

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How to Cite

Pauline Kay Lund. Insulin‐Like Growth Factors: Gene Structure and Regulation. Compr Physiol 2011, Supplement 24: Handbook of Physiology, The Endocrine System, Hormonal Control of Growth: 537-571. First published in print 1999. doi: 10.1002/cphy.cp070518