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

描述（由申请人提供）：维生素A代谢物全反式维甲酸（RA）显示出有效的抗癌活性，临床上用于治疗某些癌症。已经确定RA通过激活RAR抑制癌细胞生长，RAR是配体激活的转录因子的核受体家族的成员。细胞RA结合蛋白II（CRABP-II）支持RA对RAR的激活，CRABP-II是一种小的可溶性蛋白，其通过将RA从胞质溶胶递送到核RAR，促进受体的连接并增强其转录活性。先前的研究证实，CRABP-II在包括乳腺癌和前列腺癌在内的各种癌症中作为肿瘤抑制因子发挥作用。有趣的是，我们最近的观察表明，除了其作为RA载体的既定作用外，CRABP-II还参与转录后基因沉默的调节。这些数据表明，CRABP-II直接与HuR，从果蝇到人的动物中转录稳定性的最佳表征调节剂相关，并且它显着增强HuR稳定靶mRNA的能力。观察进一步表明，CRABP-II？HuR复合物响应于RA而解离。这些发现揭示了一种新的RA控制活性的CRABP-II。本研究旨在探讨CRABP-II与HuR在稳定mRNA方面合作的分子基础，并探讨这种合作在乳腺癌生物学中的参与。这些研究的结果将提供重要的见解，以前未知的非基因组功能的RA，以及到一个新的机制，调节转录稳定的细胞。这些研究还将调查CRABP-II抑制乳腺癌生长的可能性，其部分是通过蛋白质调节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.