Opposing effects of retinoic acid on cell growth result from alternate activation of two different nuclear receptors
Opposing effects of retinoic acid on cell growth result from alternate activation of two different nuclear receptors
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DOI：
10.1016/j.cell.2007.02.050
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发表时间：
2007-05-18
期刊：
影响因子：
64.5
通讯作者：
Noy, Noa
中科院分区：
文献类型：
--
作者：
Schug, Thaddeus T.;Berry, Daniel C.;Noy, Noa
视黄酸（RA）对核受体RAR的转录激活通常导致细胞生长的抑制。然而，在某些组织中，RA促进细胞存活和增生，这些活动不太可能由RAR介导。在这里，我们表明，除了通过RAR发挥作用，RA激活“孤儿”核受体PPAR β/δ，这反过来又诱导促生存基因的表达。RA在两种受体之间的分配受细胞内脂质结合蛋白CRABP-II和FABP 5的调节。这些蛋白质分别特异性地将RA从胞质溶胶递送至核RAR和PPAR β/δ，从而选择性地增强其同源受体的转录活性。因此，RA通过RAR发挥作用，并且在具有高CRABP-II/FABP 5比率的细胞中是促凋亡剂，但它通过PPAR β/δ发出信号，并促进高度表达FABP 5的细胞的存活。因此，RA对细胞生长的相反作用源自两种不同核受体的交替激活。
Transcriptional activation of the nuclear receptor RAR by retinoic acid (RA) often leads to inhibition of cell growth. However, in some tissues, RA promotes cell survival and hyperplasia, activities that are unlikely to be mediated by RAR. Here, we show that, in addition to functioning through RAR, RA activates the "orphan" nuclear receptor PPAR beta/delta, which, in turn, induces the expression of prosurvival genes. Partitioning of RA between the two receptors is regulated by the intracellular lipid binding proteins CRABP-II and FABP5. These proteins specifically deliver RA from the cytosol to nuclear RAR and PPAR beta/delta, respectively, thereby selectively enhancing the transcriptional activity of their cognate receptors. Consequently, RA functions through RAR and is a proapoptotic agent in cells with high CRABP-II/FABP5 ratio, but it signals through PPAR beta/delta and promotes survival in cells that highly express FABP5. Opposing effects of RA on cell growth thus emanate from alternate activation of two different nuclear receptors.