视黄酸对细胞生长的相反作用源于两种不同核受体的交替激活。
Opposing effects of retinoic acid on cell growth result from alternate activation of two different nuclear receptors.
作者信息
Schug Thaddeus T, Berry Daniel C, Shaw Natacha S, Travis Skylar N, Noy Noa
机构信息
Division of Nutritional Sciences, Cornell University, Ithaca, NY 14850, USA.
出版信息
Cell. 2007 May 18;129(4):723-33. doi: 10.1016/j.cell.2007.02.050.
Abstract
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 PPARbeta/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 PPARbeta/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 PPARbeta/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.
摘要
视黄酸（RA）对核受体RAR的转录激活通常会导致细胞生长受到抑制。然而，在某些组织中，RA可促进细胞存活和增生，而这些活动不太可能由RAR介导。在此，我们表明，除了通过RAR发挥作用外，RA还可激活“孤儿”核受体PPARβ/δ，进而诱导促存活基因的表达。细胞内脂质结合蛋白CRABP-II和FABP5可调节RA在这两种受体之间的分配。这些蛋白分别将RA从胞质溶胶特异性地递送至核RAR和PPARβ/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，在CRABP-II/FABP5比值较高的细胞中是一种促凋亡剂，但它通过PPARβ/δ发出信号，并在高表达FABP5的细胞中促进存活。因此，RA对细胞生长的相反作用源于两种不同核受体的交替激活。
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