![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
I Chung and E Bresnick
Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, New Hampshire, USA.
Cytochrome P4501A2 (CYP1A2) is a member of the cytochrome P450 family that is involved in phase I drug metabolism in vertebrates. To understand how the constitutive expression of the human CYP1A2 gene is regulated, its 5' flanking region was analyzed. The promoter activity of a human CYP1A2 gene sequence [base pairs (bp) -3203 to +58 bp] was measured in transiently transfected HepG2 cells using fusion constructs containing the luciferase reporter gene. Using 5'-end deletion analysis, two functionally important cis elements, i.e., a proximal 42- bp DNA from bp -72 to bp -31 and a distal 259-bp DNA from bp -2352 to bp -2094, were identified. The proximal sequence (bp -72 to -31) contained CCAAT and GC boxes, with which well characterized transcription factors such as nuclear factor-1/CCAT transcription factor and simian virus 40 promoter factor-1 could interact. With regard to the 259-bp fragment (bp -2352 to bp -2094), gel mobility shift analyses with HepG2 nuclear lysates indicated high affinity, specific interactions of several trans-acting factors. Three protein binding sites within the 259-bp fragment were identified by DNase 1 footprinting analysis; these sites contained activator protein-1, nuclear factor-E1.7, and one-half hepatic nuclear factor-1 (HNF-1) binding consensus sequences. Only the region from bp -2124 to bp -2098, in which the HNF-1 binding site was located, was markedly protected by a HepG2 nuclear extract, compared with a MCF7 human breast cancer nuclear extract. These results suggested that the 259-bp DNA fragment contained positive regulator binding sites and HNF-1 could contribute to the liver-specific expression of human CYP1A2.
This article has been cited by other articles:
|
|
 |
|
  W. Zhang, B. Moorthy, M. Chen, K. Muthiah, R. Coffee, A. F. Purchio, and D. B. West A Cyp1a2-Luciferase Transgenic CD-1 Mouse Model: Responses to Aryl Hydrocarbons Similar to the Humanized AhR Mice Toxicol. Sci., November 1, 2004; 82(1): 297 - 307. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Aklillu, J. A. Carrillo, E. Makonnen, K. Hellman, M. Pitarque, L. Bertilsson, and M. Ingelman-Sundberg Genetic Polymorphism of CYP1A2 in Ethiopians Affecting Induction and Expression: Characterization of Novel Haplotypes with Single-Nucleotide Polymorphisms in Intron 1 Mol. Pharmacol., September 1, 2003; 64(3): 659 - 669. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. N. Hines, Z. Luo, T. Cresteil, X. Ding, R. A. Prough, J. L. Fitzpatrick, S. L. Ripp, K. C. Falkner, N.-L. Ge, A. Levine, et al. Molecular Regulation of Genes Encoding Xenobiotic-Metabolizing Enzymes: Mechanisms Involving Endogenous Factors Drug Metab. Dispos., April 13, 2001; 29(5): 623 - 633. [Abstract] [Full Text]
|
|
|
|
 |
|
 J. Zhang, Q.-Y. Zhang, J. Guo, Y. Zhou, and X. Ding Identification and Functional Characterization of a Conserved, Nuclear Factor 1-like Element in the Proximal Promoter Region of CYP1A2 Gene Specifically Expressed in the Liver and Olfactory Mucosa J. Biol. Chem., March 17, 2000; 275(12): 8895 - 8902. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Zhang, J. M. Shields, K. Sogawa, Y. Fujii-Kuriyama, and V. W. Yang The Gut-enriched Kruppel-like Factor Suppresses the Activity of the CYP1A1 Promoter in an Sp1-dependent Fashion J. Biol. Chem., July 10, 1998; 273(28): 17917 - 17925. [Abstract] [Full Text] [PDF]
|
|
 |
 |
 |
|
 |
 |
 |
