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       报告题目：RNPC1, a RNA-binding protein and a target of the p53 family, is a key regulator of the p53 tumour suppressor pathway.

　　报告人：Xinbin Chen M.D , Ph.D.

　　时间：2009年6月25日（星期四）下午2：00

　　地点：医学部会议中心205室

　　主持人：周春燕教授（北京大学JDB电子官方网站生物化学与分子生物学系教授）

　　报告人简介：

　　Professor of Comparative Oncology

　　University of California at Davis

　　Honors and Awards

     1.     World Bank Graduate Student Fellowship, 1985 – 1987

     2.     American Cancer Society Postdoctoral Fellowship, 1994

     3.     Department of Defense Breast Cancer Research Program Postdoctoral Fellowship, 1994 – 1997

     4.     DOD Breast Cancer Research Program Career Development Award, 1997 – 2001

     5.     Distinguished Teaching Award, School of Graduate Studies, Medical College of Georgia, 2000

　　Abstract

　　P21, a cyclin-dependent kinase inhibitor, is transcriptionally regulated by the p53 family to induce cell cycle arrest.  P21 is also regulated post-transcriptionally upon DNA damage in a p53-dependent manner, but the mechanism is uncertain.  Here, we found that RNPC1, a RNA-binding protein and a target of the p53 family, is required for maintaining the stability of the basal and stress-induced p21 transcript.  Specifically, we showed that RNPC1 is induced by the p53 family and DNA damage in a p53-dependent manner.  The RNPC1 gene encodes at least two alternative spliced isoforms, RNPC1a and RNPC1b, both of which contain an intact RNA recognition motif.  Interestingly, we found that RNPC1a, but not RNPC1b, induces cell cycle arrest in G1 although both isoforms are expressed in the nucleus and cytoplasm.  In addition, we found that while both isoforms directly bind to the 3’-untranslated region in p21 transcript, only RNPC1a is able to stabilize both the basal and stress-induced p21 transcripts.  Conversely, RNPC1a knockdown destabilizes p21 transcript.  Moreover, we found that RNPC1a is required to maintain the stability of p21 transcript induced by p53.

　　In addition to regulating p21, we also found that RNPC1 plays a role in p53 expression.  We found that overexpression of RNPC1 inhibited, whereas knockdown of RNPC1 increased, p53 expression.  Interestingly, under normal conditions, RNPC1 inhibited the cap-dependent p53 translation by binding to p53 mRNA and preventing eIF4E from binding to p53 mRNA.  Under stress conditions, RNPC1 inhibited the cap-independent p53 translation by directly binding to, and repressing the activity of, the internal ribosomal entry site (IRES) in p53 mRNA.  Consistent with these, RNPC1 was unable to inhibit p53 translation upon eIF4E knockdown and its RNA-binding activity was required for preventing eIF4E from binding p53 mRNA and for inhibiting p53 IRES activity.  Moreover, we showed that knockdown of RNPC1 inhibited cell proliferation in a p53-dependent manner.  Thus, we identify a novel p53-RNPC1 feedback loop through translational regulations.

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