This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Brooks, A R Articles by Levy-Wilson, B Search for Related Content PubMed PubMed Citation Articles by Brooks, A R Articles by Levy-Wilson, B

Hepatocyte nuclear factor 1 and C/EBP are essential for the activity of the human apolipoprotein B gene second-intron enhancer.

Gladstone Institute of Cardiovascular Disease, Cardiovascular Research Institute, San Francisco, California.

ABSTRACT

The tissue-specific transcriptional enhancer of the human apolipoprotein B gene contains multiple protein-binding sites spanning 718 bp. Most of the enhancer activity is found in a 443-bp fragment (+621 to +1064) that is located entirely within the second intron of the gene. Within this fragment, a 147-bp region (+806 to +952) containing a single 97-bp DNase I footprint exhibits significant enhancer activity. We now report that this footprint contains four distinct protein-binding sites that have the potential to bind nine distinct liver nuclear proteins. One of these proteins was identified as hepatocyte nuclear factor 1 (HNF-1), which binds with relatively low affinity to the 5' half of a 20-bp palindrome located at the 5' end of the large footprint. A binding site for C/EBP (or one of the related proteins that recognize similar sequences) was identified in the center of the 97-bp footprint. This binding site is coincident or overlaps with the binding sites for five other proteins, two of which appear to be distinct from the C/EBP-related family of proteins. The binding site for a nuclear factor designated protein I is located between the HNF-1 and C/EBP binding sites. Finally, the 3'-most 15 bp of the footprinted sequence contain a binding site for another nuclear protein, which we have called protein II. Mutations that abolish the binding of either HNF-1, protein II, or the C/EBP-related proteins severely reduce enhancer activity. However, deletion experiments demonstrated that neither the HNF-1-binding site alone, nor the combination of binding sites for HNF-1, protein I, and C/EBP, nor the C/EBP-binding site plus the protein II-binding site is sufficient to enhance transcription from a strong apolipoprotein B promoter. Rather, HNF-1 and C/EBP act synergistically with protein II to enhance transcription of the apolipoprotein B gene.

This article has been cited by other articles:

• Tanaka, T., Tomaru, Y., Nomura, Y., Miura, H., Suzuki, M., Hayashizaki, Y. (2004). Comprehensive search for HNF-1{beta}-regulated genes in mouse hepatoma cells perturbed by transcription regulatory factor-targeted RNAi. Nucleic Acids Res 32: 2740-2750 [Abstract] [Full Text]  
• Gregori, C., Porteu, A., Mitchell, C., Kahn, A., Pichard, A.-L. (2002). In Vivo Functional Characterization of the Aldolase B Gene Enhancer. J. Biol. Chem. 277: 28618-28623 [Abstract] [Full Text]  
• Langmann, T., Porsch-Ozcurumez, M., Heimerl, S., Probst, M., Moehle, C., Taher, M., Borsukova, H., Kielar, D., Kaminski, W. E., Dittrich-Wengenroth, E., Schmitz, G. (2002). Identification of Sterol-independent Regulatory Elements in the Human ATP-binding Cassette Transporter A1 Promoter. ROLE OF Sp1/3, E-BOX BINDING FACTORS, AND AN ONCOSTATIN M-RESPONSIVE ELEMENT. J. Biol. Chem. 277: 14443-14450 [Abstract] [Full Text]  
• Schrem, H., Klempnauer, J., Borlak, J. (2002). Liver-Enriched Transcription Factors in Liver Function and Development. Part I: The Hepatocyte Nuclear Factor Network and Liver-Specific Gene Expression. Pharmacol. Rev. 54: 129-158 [Abstract] [Full Text]  
• Hegele, R. A., Cao, H., Harris, S. B., Hanley, A. J. G., Zinman, B., Connelly, P. W. (2000). The Private Hepatocyte Nuclear Factor-1{alpha} G319S Variant Is Associated With Plasma Lipoprotein Variation in Canadian Oji-Cree. Arterioscler. Thromb. Vasc. Bio. 20: 217-222 [Abstract] [Full Text]  
• Hansen, A. J., Lee, Y.-H., Sterneck, E., Gonzalez, F. J., Mackenzie, P. I. (1998). C/EBPalpha Is a Regulator of the UDP Glucuronosyltransferase UGT2B1 Gene. Mol. Pharmacol. 53: 1027-1033 [Abstract] [Full Text]  
• Nielsen, L. B., McCormick, S. P. A., Pierotti, V., Tam, C., Gunn, M. D., Shizuya, H., Young, S. G. (1997). Human Apolipoprotein B Transgenic Mice Generated with 207- and 145-Kilobase Pair Bacterial Artificial Chromosomes. EVIDENCE THAT A DISTANT 5'-ELEMENT CONFERS APPROPRIATE TRANSGENE EXPRESSION IN THE INTESTINE. J. Biol. Chem. 272: 29752-29758 [Abstract] [Full Text]  
• Cianflone, K., Zhang, Z., Vu, H., Kohen-Avramoglu, R., Kalant, D., Sniderman, A. D. (1996). The Effect of Individual Amino Acids on ApoB100 and Lp(a) Secretion by HepG2 Cells. J. Biol. Chem. 271: 29136-29145 [Abstract] [Full Text]  
• Kardassis, D., Laccotripe, M., Talianidis, I., Zannis, V. (1996). Transcriptional Regulation of the Genes Involved in Lipoprotein Transport : The Role of Proximal Promoters and Long-range Regulatory Elements and Factors in Apolipoprotein Gene Regulation. Hypertension 27: 980-1008 [Full Text]  
• Lee, S.-Y., Nagy, B. P., Brooks, A. R., Wang, D.-M., Paulweber, B., Levy-Wilson, B. (1996). Members of the Caudal Family of Homeodomain Proteins Repress Transcription from the Human Apolipoprotein B Promoter in Intestinal Cells. J. Biol. Chem. 271: 707-718 [Abstract] [Full Text]  
• Erdmann, D., Heim, J. (1995). Orphan Nuclear Receptor HNF-4 Binds to the Human Coagulation Factor VII Promoter. J. Biol. Chem. 270: 22988-22996 [Abstract] [Full Text]  
• Antes, T. J., Goodart, S. A., Huynh, C., Sullivan, M., Young, S. G., Levy-Wilson, B. (2000). Identification and Characterization of a 315-Base Pair Enhancer, Located More than 55 Kilobases 5' of the Apolipoprotein B Gene, That Confers Expression in the Intestine. J. Biol. Chem. 275: 26637-26648 [Abstract] [Full Text]