Distinct roles for cellular retinoic acid-binding proteins I and II in regulating signaling by retinoic acid
Distinct roles for cellular retinoic acid-binding proteins I and II in regulating signaling by retinoic acid
复制标题
DOI：
10.1074/jbc.274.34.23695
复制
发表时间：
1999-08-20
影响因子：
4.8
通讯作者：
Noy, N
中科院分区：
文献类型：
--
作者：
Dong, D;Ruuska, SE;Noy, N
视黄酸(RA)在哺乳动物细胞中的多效性是由两类蛋白质介导的：视黄酸受体(RAR)和细胞内视黄酸结合蛋白(CRABP-I和CRABP-II)。在COS-7细胞中，CRABP-II的表达，而不是CRABP-I的表达，显著地促进了RAR介导的报告基因的转录激活。CRABP-I或CRABP-II与RA形成的络合物的平衡解离常数相差2倍。因此，这两种蛋白质对反式激活的不同影响不太可能源于不同的配体结合亲和力。因此，我们直接研究了RA从CRABP向RAR转移的机制。RA从CRABP-II到RAR的移动速率常数强烈依赖于受体的浓度，而不是从CRABP-I移动到RAR。这些数据表明，RA从CRABP-I转移到RAR涉及到配体从结合蛋白中解离，然后与受体结合。相反，RA从CRABP-II到受体的运动是由CRABP-II和RAR之间直接相互作用的机制促进的，这些发现揭示了CRABP-I和CRABP-II之间显著的功能差异，并指出了CRABP-II可以调节RA转录活性的新机制。
The pleiotropic effects of retinoic acid (RA) in mammalian cells are mediated by two classes of proteins: the retinoic acid receptors (RAR) and cellular retinoic acid-binding proteins (CRABP-I and CRABP-II), Here we show that expression of CRABP-II, but not CRABP-I, markedly enhanced RAR-mediated transcriptional activation of a reporter gene in COS-7 cells. The equilibrium dissociation constants of complexes of CRABP-I or CRABP-II with RA were found to differ by 2-fold. It is thus unlikely that the distinct effects of the two proteins on transactivation stem from differential ligand-binding affinities. The mechanisms by which RA transfers from the CRABPs to RAR were thus investigated directly. The rate constant for movement of RA from CRABP-II, but not from CRABP-I, to RAR strongly depended on the concentration of the acceptor. The data suggest that transfer of RA from CRABP-I to RAR involves dissociation of the ligand from the binding protein, followed by association with the receptor. In contrast, movement of RA from CRABP-II to the receptor is facilitated by a mechanism that involves direct interactions between CRABP-II and RAR, These findings reveal a striking functional difference between CRABP-I and CRABP-II, and point at a novel mechanism by which the transcriptional activity of RA can be regulated by CRABP-II.