Molecular Endocrinology, Vol 8, 1636-1645, Copyright © 1994 by Endocrine Society

ARTICLES

Expression of the insulin-like growth factor I gene is stimulated by the liver-enriched transcription factors C/EBP alpha and LAP

LA Nolten, FM van Schaik, PH Steenbergh and JS Sussenbach
Laboratory for Physiological Chemistry, Utrecht University, The Netherlands.

The expression of the human insulin-like growth factor I (hIGF-I) gene is regulated in a developmental stage- and tissue-specific manner. Postnatally, the liver becomes the main endocrine source of this important growth factor. The hIGF-I gene contains two alternatively used leader exons, exon 1 and exon 2. In human adult liver, exon 1 sequences are represented in about 80% of the transcripts. In this study we have investigated the role of promoter 1 (P1), located upstream of leader exon 1, in the tissue-specific expression of the IGF- I gene in human adult liver. Factors involved in this process have not been described to date. In this report we show, employing transient transfection experiments in Hep3B cells, that two liver-enriched transcription factors, CCAAT/enhancer binding protein alpha (C/EBP alpha) and liver-enriched activating protein (LAP), enhance the activity of IGF-I P1. DNase I footprinting experiments demonstrate that a C/EBP-LAP binding site is located 119 base pairs upstream of the major transcription start site in exon 1. Comparison with other C/EBP- LAP binding sites reveals that the binding site in P1 is a high affinity binding site. Mutations of the C/EBP-LAP binding site completely abolished the enhancing effect of C/EBP alpha and LAP, indicating that their activating signal is indeed conferred by this binding site. These results suggest that both C/EBP alpha and LAP play important roles in the liver-specific expression of the hIGF-I gene and provide the first clues in the elucidation of its complicated developmental stage- and tissue-specific expression pattern.

This article has been cited by other articles:

				A. S. McLellan, T. Kealey, and K. Langlands An E box in the exon 1 promoter regulates insulin-like growth factor-I expression in differentiating muscle cells Am J Physiol Cell Physiol, August 1, 2006; 291(2): C300 - C307. [Abstract] [Full Text] [PDF]

				K. Karaya, S. Mori, H. Kimoto, Y. Shima, Y. Tsuji, H. Kurooka, S. Akira, and Y. Yokota Regulation of Id2 expression by CCAAT/enhancer binding protein {beta} Nucleic Acids Res., April 4, 2005; 33(6): 1924 - 1934. [Abstract] [Full Text] [PDF]

				Y. Umayahara, Y. Kajimoto, Y. Fujitani, S.-i. Gorogawa, T. Yasuda, A. Kuroda, K. Ohtoshi, S. Yoshida, D. Kawamori, Y. Yamasaki, et al. Protein Kinase C-dependent, CCAAT/Enhancer-binding Protein beta -mediated Expression of Insulin-like Growth Factor I Gene J. Biol. Chem., May 3, 2002; 277(18): 15261 - 15270. [Abstract] [Full Text] [PDF]

				E. N. Kaytor, J. L. Zhu, C.-I Pao, and L. S. Phillips Physiological Concentrations of Insulin Promote Binding of Nuclear Proteins to the Insulin-Like Growth Factor I Gene Endocrinology, March 1, 2001; 142(3): 1041 - 1049. [Abstract] [Full Text] [PDF]

				L. Wang, X. Wang, and M. L. Adamo Two Putative GATA Motifs in the Proximal Exon 1 Promoter of the Rat Insulin-Like Growth Factor I Gene Regulate Basal Promoter Activity Endocrinology, March 1, 2000; 141(3): 1118 - 1126. [Abstract] [Full Text] [PDF]

				J.-L. Zhu, C.-I Pao, E. Hunter Jr., K.-w. M. Lin, G.-j. Wu, and L. S. Phillips Identification of Core Sequences Involved in Metabolism-Dependent Nuclear Protein Binding to the Rat Insulin-Like Growth Factor I Gene Endocrinology, October 1, 1999; 140(10): 4761 - 4771. [Abstract] [Full Text]

				Y. Kobayashi, C. K. Boyd, C. J. Bracken, W. R. Lamberson, D. H. Keisler, and M. C. Lucy Reduced Growth Hormone Receptor (GHR) Messenger Ribonucleic Acid in Liver of Periparturient Cattle Is Caused by a Specific Down-Regulation of GHR 1A That Is Associated with Decreased Insulin-Like Growth Factor I Endocrinology, September 1, 1999; 140(9): 3947 - 3954. [Abstract] [Full Text]

				W. D. Rees, S. M. Hay, N. C. Fontanier-Razzaq, C. Antipatis, and D. N. Harries Expression of the Growth Arrest Genes (GAS and GADD) Changes during Organogenesis in the Rat Fetus J. Nutr., August 1, 1999; 129(8): 1532 - 1536. [Abstract] [Full Text]

				J. M. Brameld, R. S. Gilmour, and P. J. Buttery Glucose and Amino Acids Interact with Hormones to Control Expression of Insulin-Like Growth Factor-I and Growth Hormone Receptor mRNA in Cultured Pig Hepatocytes J. Nutr., July 1, 1999; 129(7): 1298 - 1306. [Abstract] [Full Text]

				C. Agarwal, T. Efimova, J. F. Welter, J. F. Crish, and R. L. Eckert CCAAT/Enhancer-binding Proteins. A ROLE IN REGULATION OF HUMAN INVOLUCRIN PROMOTER RESPONSE TO PHORBOL ESTER J. Biol. Chem., March 5, 1999; 274(10): 6190 - 6194. [Abstract] [Full Text] [PDF]

				Y.-H. Lee, B. Sauer, and F. J. Gonzalez Laron Dwarfism and Non-Insulin-Dependent Diabetes Mellitus in the Hnf-1alpha Knockout Mouse Mol. Cell. Biol., May 1, 1998; 18(5): 3059 - 3068. [Abstract] [Full Text]

				Y. Umayahara, C. Ji, M. Centrella, P. Rotwein, and T. L. McCarthy CCAAT/Enhancer-binding Protein delta  Activates Insulin-like Growth Factor-I Gene Transcription in Osteoblasts. IDENTIFICATION OF A NOVEL CYCLIC AMP SIGNALING PATHWAY IN BONE J. Biol. Chem., December 12, 1997; 272(50): 31793 - 31800. [Abstract] [Full Text] [PDF]

				X. Wang, Y. Yang, and M. L. Adamo Characterization of the Rat Insulin-Like Growth Factor I Gene Promoters and Identification of a Minimal Exon 2 Promoter Endocrinology, April 1, 1997; 138(4): 1528 - 1536. [Abstract] [Full Text] [PDF]

				L. A. Nolten, 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., December 13, 1996; 271(50): 31846 - 31854. [Abstract] [Full Text] [PDF]

				C.-I Pao, K.-w. M. Lin, J.-l. Zhu, G.-j. Wu, P. K. Farmer, and L. S. Phillips In Vitro Transcription of the Rat Insulin-like Growth Factor-I Gene J. Biol. Chem., April 12, 1996; 271(15): 8667 - 8674. [Abstract] [Full Text] [PDF]

				C.-I Pao, J.-l. Zhu, D. G. Robertson, K.-w. M. Lin, P. K. Farmer, S. Begovic, G.-j. Wu, and L. S. Phillips Transcriptional Regulation of the Rat Insulin-like Growth Factor-I Gene Involves Metabolism-dependent Binding of Nuclear Proteins to a Downstream Region J. Biol. Chem., October 20, 1995; 270(42): 24917 - 24923. [Abstract] [Full Text] [PDF]

				B. Fournier, S. Gutzwiller, T. Dittmar, G. Matthias, P. Steenbergh, and P. Matthias Estrogen Receptor (ER)-alpha , but Not ER-beta , Mediates Regulation of the Insulin-like Growth Factor I Gene by Antiestrogens J. Biol. Chem., September 14, 2001; 276(38): 35444 - 35449. [Abstract] [Full Text] [PDF]