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 Hu, J Articles by Isom, H C Search for Related Content PubMed PubMed Citation Articles by Hu, J Articles by Isom, H C

Suppression of albumin enhancer activity by H-ras and AP-1 in hepatocyte cell lines.

Department of Microbiology and Immunology, Pennsylvania State University, College of Medicine, Hershey 17033.

ABSTRACT

We demonstrated, using a transient transfection assay, that the albumin enhancer increased the expression of the albumin promoter in a highly differentiated, simian virus 40 (SV40)-immortalized hepatocyte cell line, CWSV1, but was not functional in two ras-transformed cell lines (NR3 and NR4) derived from CWSV1 by stable transfection with the T24ras oncogene. A transient cotransfection assay showed that T24ras and normal c-Ha-ras were each able to inhibit the activity of the albumin enhancer in an immortal hepatocyte cell line. DNase I footprinting and gel mobility shift assays demonstrated that the DNA binding activities specific to the albumin enhancer were not decreased in the ras-transformed cells. ras also did not diminish the expression of HNF1 alpha, C/EBP alpha, HNF3 alpha, HNF3 beta, or HNF3 gamma but did significantly increase AP-1 binding activity. Three AP-1 binding sites were identified within the albumin enhancer, and DNA binding activities specific to these AP-1 sites were induced in the ras-transformed hepatocytes. Subsequent functional assays showed that overexpression of c-jun and c-fos inhibited the activity of the albumin enhancer. Site-directed mutagenesis of the AP-1 binding sites in the albumin enhancer partially abrogated the suppressing effect of ras and c-jun/c-fos on the enhancer. These functional studies therefore supported the results of the structural studies with AP-1. We conclude that the activity of the albumin enhancer is subject to regulation by ras signaling pathways and that the effect of ras on the albumin enhancer activity may be mediated by AP-1.

This article has been cited by other articles:

• van Greevenbroek, M. M. J., Vermeulen, V. M. M-J., de Bruin, T. W. A. (2004). Identification of novel molecular candidates for fatty liver in the hyperlipidemic mouse model, HcB19. J. Lipid Res. 45: 1148-1154 [Abstract] [Full Text]  
• Suzuki, A., Iwama, A., Miyashita, H., Nakauchi, H., Taniguchi, H. (2003). Role for growth factors and extracellular matrix in controlling differentiation of prospectively isolated hepatic stem cells. Development 130: 2513-2524 [Abstract] [Full Text]  
• Gualdi, R, Bossard, P, Zheng, M, Hamada, Y, Coleman, J R, Zaret, K S (1996). Hepatic specification of the gut endoderm in vitro: cell signaling and transcriptional control.. Genes Dev. 10: 1670-1682 [Abstract]  
• Bois-Joyeux, B., Denissenko, M., Thomassin, Hélèn., Guesdon, S., Ikonomova, R., Bernuau, D., Feldmann, Gér., Danan, J.-L. (1995). The c- jun Proto-oncogene Down-regulates the Rat [IMAGE]-Fetoprotein Promoter in HepG2 Hepatoma Cells without Binding to DNA. J. Biol. Chem. 270: 10204-10211 [Abstract] [Full Text]