DOWN-REGULATION OF NUCLEAR ARYL-HYDROCARBON RECEPTOR DNA-BINDING AND TRANSACTIVATION FUNCTIONS - REQUIREMENT FOR A LABILE OR INDUCIBLE FACTOR

被引:46
作者
REICK, M [1 ]
ROBERTSON, RW [1 ]
PASCO, DS [1 ]
FAGAN, JB [1 ]
机构
[1] MAHARISHI INT UNIV,MOLEC BIOL LAB,FAIRFIELD,IA 52557
关键词
D O I
10.1128/MCB.14.9.5653
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Aryl hydrocarbons (AHs) such as 2,3,7,8-tetrachlorodibenzo-p-dioxin and benzo[a]pyrene activate the sequence-specific DNA-binding activity of the AH receptor. In the rat hepatocyte-derived cell line LCS7, DNA-binding activity peaked after 30 min and was then down-regulated, reaching negligible levels by 2 h. Down-regulation could be blocked, and DNA-binding activity maintained at maximum for many hours by inhibiting protein or RNA synthesis, implying that down-regulation is a mediated process requiring a labile or inducible protein. CYP1A1 transcription and in vivo DNA-protein interactions at xenobiotic response elements were down-regulated in parallel with DNA-binding activity in nuclear extracts, and these changes could also be blocked by inhibitors of protein synthesis. The correlation between AH receptor DNA-binding activity, intensity of in vivo footprints at xenobiotic response elements, and CYP1A1 transcription rate implies that down-regulation of AH receptor DNA-binding activity is important in regulating CYP1A1 transcription and that receptor is required continuously to maintain transcription. This correlation extends to the murine hepatoma cell line Hepa-1c1c7, in which slower kinetics of activation and down-regulation of CYP1A1 transcription paralleled slower activation and down-regulation of AH receptor DNA-binding activity. The difference in kinetics between cell lines also implies that AH receptor DNA-binding activity is modulated by a mechanism that may be influenced by cell-specific regulatory pathways. The above observations in conjunction with mixing experiments and comparisons of cytoplasmic and nuclear extracts indicate that down-regulation of AW receptor DNA-binding activity is probably due either to degradation or to conversion of the receptor to a form that is inactive in both DNA binding and transactivation.
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页码:5653 / 5660
页数:8
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