Skip to main content
Biochemical Journal logoLink to Biochemical Journal
. 1991 Dec 1;280(Pt 2):439–444. doi: 10.1042/bj2800439

Identification of a novel transcription unit in the human insulin-like growth factor-II gene.

K Ikejiri 1, T Wasada 1, K Haruki 1, N Hizuka 1, Y Hirata 1, M Yamamoto 1
PMCID: PMC1130567  PMID: 1720956

Abstract

The human insulin-like growth factor-II (hIGF-II) gene has until now been thought to be composed of eight exons, including three independent leader exons. In the present study two additional exons, one leader exon and one alternatively used ordinate exon, have been newly identified. They were abundantly expressed in human histiocytoma tissue, generating mRNA species of about 5.0 kb in length. The new leader exon shows significant sequence similarity with the rE1 exon, previously reported to be transcribed only in the rat, and is mapped at nearly the same genomic location as in the rat. On the other hand, sequence similarity with another exon in the corresponding region of the rat genome was also found. It was, however, obvious that the rat sequence would not work as an active exon, since both splice acceptor and donor sites were deviated considerably from the consensus sequences. It has thus become apparent that the complex transcription unit of a single-copy hIGF-II gene comprises at least 10 exons, including four leader exons, one alternative exon and three common protein-coding exons.

Full text

PDF
439

Images in this article

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Blatt J., White C., Dienes S., Friedman H., Foley T. P., Jr Production of an insulin-like growth factor by osteosarcoma. Biochem Biophys Res Commun. 1984 Aug 30;123(1):373–376. doi: 10.1016/0006-291x(84)90423-6. [DOI] [PubMed] [Google Scholar]
  2. Breathnach R., Chambon P. Organization and expression of eucaryotic split genes coding for proteins. Annu Rev Biochem. 1981;50:349–383. doi: 10.1146/annurev.bi.50.070181.002025. [DOI] [PubMed] [Google Scholar]
  3. Brown A. L., Graham D. E., Nissley S. P., Hill D. J., Strain A. J., Rechler M. M. Developmental regulation of insulin-like growth factor II mRNA in different rat tissues. J Biol Chem. 1986 Oct 5;261(28):13144–13150. [PubMed] [Google Scholar]
  4. De Larco J. E., Tadaro G. J. A human fibrosarcoma cell line producing multiplication stimulating activity (MSA)-related peptides. Nature. 1978 Mar 23;272(5651):356–358. doi: 10.1038/272356a0. [DOI] [PubMed] [Google Scholar]
  5. DeChiara T. M., Efstratiadis A., Robertson E. J. A growth-deficiency phenotype in heterozygous mice carrying an insulin-like growth factor II gene disrupted by targeting. Nature. 1990 May 3;345(6270):78–80. doi: 10.1038/345078a0. [DOI] [PubMed] [Google Scholar]
  6. Dull T. J., Gray A., Hayflick J. S., Ullrich A. Insulin-like growth factor II precursor gene organization in relation to insulin gene family. 1984 Aug 30-Sep 5Nature. 310(5980):777–781. doi: 10.1038/310777a0. [DOI] [PubMed] [Google Scholar]
  7. Evans T., DeChiara T., Efstratiadis A. A promoter of the rat insulin-like growth factor II gene consists of minimal control elements. J Mol Biol. 1988 Jan 5;199(1):61–81. doi: 10.1016/0022-2836(88)90379-8. [DOI] [PubMed] [Google Scholar]
  8. Feinberg A. P., Vogelstein B. A technique for radiolabeling DNA restriction endonuclease fragments to high specific activity. Anal Biochem. 1983 Jul 1;132(1):6–13. doi: 10.1016/0003-2697(83)90418-9. [DOI] [PubMed] [Google Scholar]
  9. Froesch E. R., Schmid C., Schwander J., Zapf J. Actions of insulin-like growth factors. Annu Rev Physiol. 1985;47:443–467. doi: 10.1146/annurev.ph.47.030185.002303. [DOI] [PubMed] [Google Scholar]
  10. Froesch E. R., Zapf J., Audhya T. K., Ben-Porath E., Segen B. J., Gibson K. D. Nonsuppressible insulin-like activity and thyroid hormones: major pituitary-dependent sulfation factors for chick embryo cartilage. Proc Natl Acad Sci U S A. 1976 Aug;73(8):2904–2908. doi: 10.1073/pnas.73.8.2904. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Frunzio R., Chiariotti L., Brown A. L., Graham D. E., Rechler M. M., Bruni C. B. 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. 1986 Dec 25;261(36):17138–17149. [PubMed] [Google Scholar]
  12. Gao F., Endo H., Yamamoto M. Length heterogeneity in rat salivary gland alpha 2 mu globulin mRNAs: multiple splice-acceptors and polyadenylation sites. Nucleic Acids Res. 1989 Jun 26;17(12):4629–4636. doi: 10.1093/nar/17.12.4629. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Graham D. E., Rechler M. M., Brown A. L., Frunzio R., Romanus J. A., Bruni C. B., Whitfield H. J., Nissley S. P., Seelig S., Berry S. Coordinate developmental regulation of high and low molecular weight mRNAs for rat insulin-like growth factor II. Proc Natl Acad Sci U S A. 1986 Jun;83(12):4519–4523. doi: 10.1073/pnas.83.12.4519. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Gray A., Tam A. W., Dull T. J., Hayflick J., Pintar J., Cavenee W. K., Koufos A., Ullrich A. Tissue-specific and developmentally regulated transcription of the insulin-like growth factor 2 gene. DNA. 1987 Aug;6(4):283–295. doi: 10.1089/dna.1987.6.283. [DOI] [PubMed] [Google Scholar]
  15. Gubler U., Hoffman B. J. A simple and very efficient method for generating cDNA libraries. Gene. 1983 Nov;25(2-3):263–269. doi: 10.1016/0378-1119(83)90230-5. [DOI] [PubMed] [Google Scholar]
  16. Han V. K., D'Ercole A. J., Lund P. K. Cellular localization of somatomedin (insulin-like growth factor) messenger RNA in the human fetus. Science. 1987 Apr 10;236(4798):193–197. doi: 10.1126/science.3563497. [DOI] [PubMed] [Google Scholar]
  17. Hattori M., Sakaki Y. Dideoxy sequencing method using denatured plasmid templates. Anal Biochem. 1986 Feb 1;152(2):232–238. doi: 10.1016/0003-2697(86)90403-3. [DOI] [PubMed] [Google Scholar]
  18. Huff K. K., Kaufman D., Gabbay K. H., Spencer E. M., Lippman M. E., Dickson R. B. Secretion of an insulin-like growth factor-I-related protein by human breast cancer cells. Cancer Res. 1986 Sep;46(9):4613–4619. [PubMed] [Google Scholar]
  19. Höppener J. W., Steenbergh P. H., Slebos R. J., de Pagter-Holthuizen P., Roos B. A., Jansen M., Van den Brande J. L., Sussenbach J. S., Jansz H. S., Lips C. J. Expression of insulin-like growth factor-I and -II genes in rat medullary thyroid carcinoma. FEBS Lett. 1987 May 4;215(1):122–126. doi: 10.1016/0014-5793(87)80125-4. [DOI] [PubMed] [Google Scholar]
  20. Ikejiri K., Ueno T., Matsuguchi T., Takahashi K., Endo H., Yamamoto M. The primary structure of the rat insulin-like growth factor II gene region. Biochim Biophys Acta. 1990 Jul 30;1049(3):350–353. doi: 10.1016/0167-4781(90)90110-n. [DOI] [PubMed] [Google Scholar]
  21. Jansen M., van Schaik F. M., van Tol H., Van den Brande J. L., Sussenbach J. S. Nucleotide sequences of cDNAs encoding precursors of human insulin-like growth factor II (IGF-II) and an IGF-II variant. FEBS Lett. 1985 Jan 7;179(2):243–246. doi: 10.1016/0014-5793(85)80527-5. [DOI] [PubMed] [Google Scholar]
  22. Lund P. K., Moats-Staats B. M., Hynes M. A., Simmons J. G., Jansen M., D'Ercole A. J., Van Wyk J. J. Somatomedin-C/insulin-like growth factor-I and insulin-like growth factor-II mRNAs in rat fetal and adult tissues. J Biol Chem. 1986 Nov 5;261(31):14539–14544. [PubMed] [Google Scholar]
  23. Matsuguchi T., Takahashi K., Ikejiri K., Ueno T., Endo H., Yamamoto M. Functional analysis of multiple promoters of the rat insulin-like factor II gene. Biochim Biophys Acta. 1990 Apr 6;1048(2-3):165–170. doi: 10.1016/0167-4781(90)90052-4. [DOI] [PubMed] [Google Scholar]
  24. Mizusawa S., Nishimura S., Seela F. Improvement of the dideoxy chain termination method of DNA sequencing by use of deoxy-7-deazaguanosine triphosphate in place of dGTP. Nucleic Acids Res. 1986 Feb 11;14(3):1319–1324. doi: 10.1093/nar/14.3.1319. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Moses A. C., Nissley S. P., Short P. A., Rechler M. M., White R. M., Knight A. B., Higa O. Z. Increased levels of multiplication-stimulating activity, an insulin-like growth factor, in fetal rat serum. Proc Natl Acad Sci U S A. 1980 Jun;77(6):3649–3653. doi: 10.1073/pnas.77.6.3649. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Padgett R. A., Grabowski P. J., Konarska M. M., Seiler S., Sharp P. A. Splicing of messenger RNA precursors. Annu Rev Biochem. 1986;55:1119–1150. doi: 10.1146/annurev.bi.55.070186.005351. [DOI] [PubMed] [Google Scholar]
  27. Rechler M. M., Nissley S. P. The nature and regulation of the receptors for insulin-like growth factors. Annu Rev Physiol. 1985;47:425–442. doi: 10.1146/annurev.ph.47.030185.002233. [DOI] [PubMed] [Google Scholar]
  28. Rechler M. M., Podskalny J. M., Goldfine I. D., Wells C. A. DNA synthesis in human fibroblasts: stimulation by insulin and by nonsuppressible insulin-like activity (NSILA-S). J Clin Endocrinol Metab. 1974 Sep;39(3):512–521. doi: 10.1210/jcem-39-3-512. [DOI] [PubMed] [Google Scholar]
  29. Reeve A. E., Eccles M. R., Wilkins R. J., Bell G. I., Millow L. J. Expression of insulin-like growth factor-II transcripts in Wilms' tumour. Nature. 1985 Sep 19;317(6034):258–260. doi: 10.1038/317258a0. [DOI] [PubMed] [Google Scholar]
  30. Rinderknecht E., Humbel R. E. Polypeptides with nonsuppressible insulin-like and cell-growth promoting activities in human serum: isolation, chemical characterization, and some biological properties of forms I and II. Proc Natl Acad Sci U S A. 1976 Jul;73(7):2365–2369. doi: 10.1073/pnas.73.7.2365. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Rotwein P. Two insulin-like growth factor I messenger RNAs are expressed in human liver. Proc Natl Acad Sci U S A. 1986 Jan;83(1):77–81. doi: 10.1073/pnas.83.1.77. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Sanger F., Nicklen S., Coulson A. R. DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci U S A. 1977 Dec;74(12):5463–5467. doi: 10.1073/pnas.74.12.5463. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Scott J., Cowell J., Robertson M. E., Priestley L. M., Wadey R., Hopkins B., Pritchard J., Bell G. I., Rall L. B., Graham C. F. Insulin-like growth factor-II gene expression in Wilms' tumour and embryonic tissues. Nature. 1985 Sep 19;317(6034):260–262. doi: 10.1038/317260a0. [DOI] [PubMed] [Google Scholar]
  34. Soares M. B., Ishii D. N., Efstratiadis A. Developmental and tissue-specific expression of a family of transcripts related to rat insulin-like growth factor II mRNA. Nucleic Acids Res. 1985 Feb 25;13(4):1119–1134. doi: 10.1093/nar/13.4.1119. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Soares M. B., Turken A., Ishii D., Mills L., Episkopou V., Cotter S., Zeitlin S., Efstratiadis A. Rat insulin-like growth factor II gene. A single gene with two promoters expressing a multitranscript family. J Mol Biol. 1986 Dec 20;192(4):737–752. doi: 10.1016/0022-2836(86)90025-2. [DOI] [PubMed] [Google Scholar]
  36. Sporn M. B., Roberts A. B. Autocrine growth factors and cancer. 1985 Feb 28-Mar 6Nature. 313(6005):745–747. doi: 10.1038/313745a0. [DOI] [PubMed] [Google Scholar]
  37. Sporn M. B., Todaro G. J. Autocrine secretion and malignant transformation of cells. N Engl J Med. 1980 Oct 9;303(15):878–880. doi: 10.1056/NEJM198010093031511. [DOI] [PubMed] [Google Scholar]
  38. Sussenbach J. S. The gene structure of the insulin-like growth factor family. Prog Growth Factor Res. 1989;1(1):33–48. doi: 10.1016/0955-2235(89)90040-9. [DOI] [PubMed] [Google Scholar]
  39. Thomas P. S. Hybridization of denatured RNA and small DNA fragments transferred to nitrocellulose. Proc Natl Acad Sci U S A. 1980 Sep;77(9):5201–5205. doi: 10.1073/pnas.77.9.5201. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Tricoli J. V., Rall L. B., Karakousis C. P., Herrera L., Petrelli N. J., Bell G. I., Shows T. B. Enhanced levels of insulin-like growth factor messenger RNA in human colon carcinomas and liposarcomas. Cancer Res. 1986 Dec;46(12 Pt 1):6169–6173. [PubMed] [Google Scholar]
  41. Ueno T., Takahashi K., Matsuguchi T., Endo H., Yamamoto M. A new leader exon identified in the rat insulin-like growth factor II gene. Biochem Biophys Res Commun. 1987 Oct 14;148(1):344–349. doi: 10.1016/0006-291x(87)91116-8. [DOI] [PubMed] [Google Scholar]
  42. Ueno T., Takahashi K., Matsuguchi T., Endo H., Yamamoto M. 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. 1988 Sep 7;950(3):411–419. doi: 10.1016/0167-4781(88)90138-8. [DOI] [PubMed] [Google Scholar]
  43. Ueno T., Takahashi K., Matsuguchi T., Ikejiri K., Endo H., Yamamoto M. Reactivation of rat insulin-like growth factor II gene during hepatocarcinogenesis. Carcinogenesis. 1988 Oct;9(10):1779–1783. doi: 10.1093/carcin/9.10.1779. [DOI] [PubMed] [Google Scholar]
  44. Van Wyk J. J., Underwood L. E., Hintz R. L., Clemmons D. R., Voina S. J., Weaver R. P. The somatomedins: a family of insulinlike hormones under growth hormone control. Recent Prog Horm Res. 1974;30(0):259–318. [PubMed] [Google Scholar]
  45. Yamamoto M., Maehara Y., Takahashi K., Endo H. Cloning of sequences expressed specifically in tumors of rat. Proc Natl Acad Sci U S A. 1983 Dec;80(24):7524–7527. doi: 10.1073/pnas.80.24.7524. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Yee D., Cullen K. J., Paik S., Perdue J. F., Hampton B., Schwartz A., Lippman M. E., Rosen N. Insulin-like growth factor II mRNA expression in human breast cancer. Cancer Res. 1988 Dec 1;48(23):6691–6696. [PubMed] [Google Scholar]
  47. Zapf J., Schoenle E., Froesch E. R. Insulin-like growth factors I and II: some biological actions and receptor binding characteristics of two purified constituents of nonsuppressible insulin-like activity of human serum. Eur J Biochem. 1978 Jun 15;87(2):285–296. doi: 10.1111/j.1432-1033.1978.tb12377.x. [DOI] [PubMed] [Google Scholar]
  48. de Pagter-Holthuizen P., Jansen M., van Schaik F. M., van der Kammen R., Oosterwijk C., Van den Brande J. L., Sussenbach J. S. The human insulin-like growth factor II gene contains two development-specific promoters. FEBS Lett. 1987 Apr 20;214(2):259–264. doi: 10.1016/0014-5793(87)80066-2. [DOI] [PubMed] [Google Scholar]

Articles from Biochemical Journal are provided here courtesy of The Biochemical Society

RESOURCES