Konta T, Xu Q, Furusu A, Nakayama K, Kitamura M
Renal Bioengineering Unit, Department of Medicine, Royal Free and University College Medical School, University College London, United Kingdom.
J Biol Chem. 2001 Apr 20;276(16):12697-701. doi: 10.1074/jbc.M011000200. Epub 2001 Jan 16.
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.
维甲酸对包括细胞增殖、分化和形态发生在内的许多生物学过程具有深远影响。我们之前报道过，全反式维甲酸（t-RA）通过抑制激活蛋白1（AP-1）信号通路保护系膜细胞免受H₂O₂诱导的细胞凋亡。其机制是抑制c-fos和c-jun的表达以及抑制c-Jun氨基末端激酶（JNK）的激活。在本报告中，我们研究了维甲酸受体（RAR）和类视黄醇X受体（RXR）在t-RA对H₂O₂处理细胞的抗凋亡作用中的参与情况。我们发现，用RAR泛拮抗剂（AGN193109）或RXR泛拮抗剂（HX531）预处理可减弱t-RA的抗凋亡作用。同样，用RAR显性负性突变体或显性负性RXR进行瞬时转染也会减弱t-RA的抗凋亡作用。RAR和RXR拮抗剂均可逆转t-RA对AP-1活性的抑制作用。然而，发现RAR和RXR在t-RA抑制AP-1成分中的作用有所不同。RAR拮抗剂可逆转t-RA对c-fos和c-jun的抑制作用，而RXR拮抗剂可逆转t-RA对c-fos的作用，但对c-jun无作用。此外，即使存在RAR和RXR拮抗剂，仍可观察到t-RA对JNK激活的抑制作用。同样，t-RA对JNK的抑制作用不受显性负性RAR或显性负性RXR过表达的影响。这些数据表明，t-RA的抗凋亡作用是由核受体依赖性和非依赖性机制共同介导的。
