Retinoic acid and CRABP-II in regulation of post transcriptional gene silencing

描述（申请人提供）：维生素A代谢物全反式视黄酸（RA）显示出有效的抗癌活性，临床上用于治疗某些癌症。众所周知，RA 通过激活 RAR 来抑制癌细胞生长，RAR 是配体激活转录因子核受体家族的成员。 RA 对 RAR 的激活得到细胞 RA 结合蛋白 II (CRABP-II) 的支持，CRABP-II 是一种小可溶性蛋白，通过将 RA 从细胞质传递到核 RAR，促进受体的连接并增强其转录活性。先前的研究表明，CRABP-II 在包括乳腺癌和前列腺癌在内的多种癌症中发挥肿瘤抑制作用。有趣的是，我们最近的观察表明，除了其作为 RA 载体的既定作用之外，CRABP-II 还参与转录后基因沉默的调节。数据表明，CRABP-II 与 HuR 直接相关，HuR 是从果蝇到人类的动物中转录稳定性最好的调节因子，并且它显着增强了 HuR 稳定靶 mRNA 的能力。观察进一步表明CRABP-II?HuR复合物响应RA而解离。这些发现揭示了 CRABP-II 的一种新的 RA 控制活性。拟议的研究旨在研究 CRABP-II 与 HuR 合作稳定 mRNA 的分子基础，并探讨这种合作在乳腺癌生物学中的作用。这些研究的结果将为了解以前未曾怀疑的 RA 非基因组功能以及调节细胞转录稳定性的新机制提供重要见解。这些研究还将调查 CRABP-II 抑制乳腺癌生长的可能性，部分是通过该蛋白调节 mRNA 稳定性的能力介导的。

DESCRIPTION (provided by applicant): The vitamin A metabolite all-trans-retinoic acid (RA) displays potent anticarcinogenic activities and is used clinically for treatment of some cancers. I is well established that RA inhibits carcinoma cell growth by activating RAR, a member of the nuclear receptor family of ligand-activated transcription factors. Activation of RAR by RA is supported by cellular RA-binding protein II (CRABP-II), a small soluble protein which, by delivering RA from the cytosol to nuclear RAR, facilitates the ligation of the receptor and enhances its transcriptional activity. Previous studies established that CRABP-II functions as a tumor suppressor in various cancers including mammary and prostate cancers. Intriguingly, our recent observations showed that, in addition to its established role as a carrier for RA, CRABP-II is involved in regulation of post-transcriptional gene silencing. The data demonstrated that CRABP-II directly associates with HuR, the best characterized regulator of transcript stability in animals from drosophila to man, and that it markedly augments the ability of HuR to stabilize target mRNAs. The observations showed further that the CRABP-II?HuR complex dissociates in response to RA. These findings reveal a novel RA-controlled activity of CRABP-II. The proposed studies aim to investigate the molecular basis for the cooperation of CRABP-II with HuR in stabilizing mRNA, and to explore the involvement of this cooperation in mammary carcinoma biology. The results of these studies will provide important insights into a previously unsuspected non-genomic function of RA as well as into a novel mechanism for regulating transcript stability in cells. The studies will also investigate the possibility that suppression o mammary carcinoma growth by CRABP-II is mediated in part through the ability of the protein to regulate mRNA stability.