Selective roles of retinoic acid receptor and retinoid X receptor in the suppression of apoptosis by all-trans-retinoic acid

被引:56
作者
Konta, T [1 ]
Xu, QH [1 ]
Furusu, A [1 ]
Nakayama, K [1 ]
Kitamura, M [1 ]
机构
[1] Royal Free & UCL, Sch Med, Dept Med, Renal Bioengn Unit,Jules Thorn Inst,Middlesex Hos, London W1T 3AA, England
关键词
D O I
10.1074/jbc.M011000200
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
Retinoic acids exert profound effects on many biological processes including cell proliferation, differentiation, and morphogenesis, We previously reported that all-trans-retinoic acid (t-RA) protected mesangial cells from H(2)O(2)-triggered apoptosis by suppressing the activator protein 1 (AP-1) pathway. It was via inhibition of c-fos and c-jun expression and suppression of c-Jun N-terminal kinase (JNK) activation. In this report, we investigated the involvement of retinoic acid receptor (RAR) and retinoid X receptor (RXR) in the antiapoptotic effect of t-RA in H(2)O(2)-exposed cells. We found that pretreatment with RAR pan-antagonist (AGN193109) or RXR pan-antagonist (HX531) attenuated the antiapoptotic effect of t-RA, Similarly, transient transfection with a dominant-negative mutant of RAR or a dominant-negative RXR diminished the antiapoptotic effect of t-RA Both RAR and RXR antagonists reversed the suppressive effect of t-RA on AP-1 activity. However, the roles of RAR and RXR in the suppression of AP-1 components by t-RA were found to be different. RAR antagonist reversed the suppressive effect of t-RA on both c-fos and c-jun, whereas RXR antagonist reversed the effect of t-RA on c-fos but not c-jun, Furthermore, suppression of JNK activation by t-RA was observed even in the presence of RAR and RXR antagonists. Consistently, suppression of JNK by t-RA was not affected by overexpression of either the dominant-negative RAR or the dominant-negative RXR, These data elucidated that the antiapoptotic effect of t-RA is mediated by both nuclear receptor-dependent and -independent mechanisms.
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页码:12697 / 12701
页数:5
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