Regulation of p53 in Mammalian Cells |
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| Air date: | Wednesday, January 23, 2008, 3:00:00 PM |
| Category: | Wednesday Afternoon Lectures |
| Runtime: | 67 minutes |
| NLM Title: | Regulation of p53 in mammalian cells [electronic resource] / Carol Prives. |
| Series: | NIH director's Wednesday afternoon lecture series |
| Author: | Prives, Carol. National Institutes of Health (U.S.) |
| Publisher: | [Bethesda, Md. : National Institutes of Health, 2008] |
| Other Title(s): | NIH director's Wednesday afternoon lecture series |
| Abstract: | (CIT): The focus of much of the work in Dr. Prives' laboratory is the functions of p53 and its negative regulator and transcriptional target, Mdm2. Two general areas are being investigated, how p53 functions as a transcription factor and the roles and regulation of Mdm2. P53 is a sequence-specific transcriptional activator of genes involved in cellular outcomes such as cell cycle arrest and apoptosis. We have identified a new co-regulator of select p53 targets, Cas/Cse1L, a protein previously shown to be involved in nuclear transport. Cas/Cse1L binds to the promoters of a subset of p53 targets and levels of Cas/Cse1L are correlated with the extent to which these genes are induced by p53. Atne p53 target promoter, PIG3, Cas/Cse1L has a long range inhibitory effect on tri-methylation of histone H3 lysine 27, a repressive modification, which could explain how Cas/Cse1L and p53 cooperate to regulate some p53 targets and apoptosis. Another project stems from our earlier finding that in some cells p53 is impaired in its ability to induce transcription from some of its target genes when cells are blocked in S phase. We have extended these findings by showing that while p53 can bind to its sites within these promoters and recruit histone acetylases, TFIID and RNA polymerase, transcription elongation by RNA polymerase is significantly reduced when the DNA replication checkpoint is activated. Our data implicate the checkpoint kinases in this block to elongation of p53 targets. Regarding our studies on Mdm2, an extensive yeast two-hybrid screen led to the identification of RPS7, a ribosomal protein that can interact with and regulate Mdm2. Ribosomal stress leads to the appearance of RPS7 in the nucleoplasm and RPS7 inhibits Mdm2 E3 ligase activity in vivo and in vitro. Our data also suggest that the Mdm2 homologue, MdmX, is involved in RPS7 repression of Mdm2. Further, ablation of RPS7 causes both increased turnover of Mdm2 and decreased p53 after treatment of cells with several genotoxic agents. Our data thus implicate ribosomal and nucleolar stress as being very important for DNA damage signaling to p53. Interestingly as well, RPS7 itself is a substrate of the Mdm2 E3 ligase activity suggesting a new circuit whereby a negative regulator of Mdm2 is itself an Mdm2 target. Dr. Prives was born in Montreal, Canada and received her BSc degree in 1962 and Ph.D. in 1966 at McGill University. After spending a year at the University of British Columbia, she did post-doctoral research at Albert Einstein College of Medicine, Bronx, N.Y. in the laboratory of Dr. J.T. August from 1968 through 1971 where she held a Damon Runyon Fellowship. In 1971 she worked in the laboratory of Dr. E. Ehrenfeld. She then went to the Weizmann Institute on a senior visiting fellowship where she worked on a project jointly sponsored by Professors Ernest Winocour and Michel Revel. In 1974 she was appointed as intermediate scientist, in 1975 she was promoted to the rank of senior scientist (equivalent to Assistant Professor in American universities) and in 1977 she was promoted to Associate Professor with tenure at the Weizmann Institute. She left Israel for a sabbatical in 1978 to work in the laboratory of Dr. George Khoury at the NIH. In 1979 she took a position as Associate Professor at the Department of Biological Sciences at Columbia University. She was awarded tenure at Columbia in 1982 and was promoted to Full Professor in 1987. In 1995 she was appointed the Da Costa Professor of Biology at Columbia. In 1996 she was the recipient of a MERIT award from the NIH and in 1998 she was awarded a Research Professorship from the American Cancer Society. In 2000 she became a member of the American Academy of Arts and Sciences and in 2005 she was elected to the Institute of Medicine. |
| Subjects: | Neoplasms--etiology Tumor Suppressor Protein p53--physiology |
| Publication Types: | Government Publications Lectures |
| Download: | Download
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| NLM Classification: | QZ 202 |
| NLM ID: | 101465446 |
| CIT File ID: | 14256 |
| CIT Live ID: | 6207 |
| Permanent link: | http://videocast.nih.gov/launch.asp?14256 |
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Enhanced Audio Podcast | 1:02:45 |
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Enhanced Video Podcast | 1:02:45 | |