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

描述(申请人提供)：维生素A代谢物全反式维甲酸(RA)显示出强大的抗癌活性，并被临床用于治疗一些癌症。众所周知，RA通过激活RAR来抑制癌细胞的生长，RAR是配体激活的转录因子核受体家族的成员。RA对RAR的激活是由细胞RA结合蛋白II(CRABP-II)支持的，CRABP-II是一种小的可溶性蛋白，通过将RA从胞浆输送到核RAR，促进受体的连接并增强其转录活性。以前的研究证实，CRABP-II在包括乳腺癌和前列腺癌在内的各种癌症中发挥肿瘤抑制作用。有趣的是，我们最近的观察表明，除了作为RA载体的既定角色外，CRABP-II还参与转录后基因沉默的调节。数据表明，CRABP-II直接与Hur结合，Hur是从果蝇到人的动物中最具特征的转录稳定调节因子，它显著增强了Hur稳定靶mRNAs的能力。观察进一步表明，CRABP-II？HUR复合体对RA的反应是解离的。这些发现揭示了CRABP-II的一种新的RA控制活性。本研究旨在探讨CRABP-II与HUR协同稳定mRNA的分子基础，并探讨这种协同作用在乳腺癌生物学中的作用。这些研究的结果将为RA以前未被怀疑的非基因组功能以及调节细胞内转录稳定性的新机制提供重要的见解。这些研究还将探讨CRABP-II抑制乳腺癌生长的可能性，部分是通过该蛋白调节mRNA稳定性的能力来实现的。

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.