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FUNCTIONAL ANALYSIS OF THE P53 TUMOR SUPPRESSOR

Award Number: R37CA040099
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/15/1985
PERIOD OF PERFORMANCE END DATE: 07/30/2013

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FUNCTIONAL ANALYSIS OF THE P53 TUMOR SUPPRESSOR - The p53 tumor suppressor gene is a major target for inactivation in human cancer. In non-stressed normal cells, the p53 protein is practically latent, owing to its being present in very low amounts and in a rather inactive molecular form. The relative lack of activity of p53 under such conditions is largely due to the action of Mdm2, which targets p53 for rapid degradation and, furthermore, maintains p53 in a complex that is incompatible with efficient performance of p53 as a transcription factor. In response to a variety of stress signals, particularly those that are closely linked with cancer (e.g. genomic damage, oncogene activation), p53 is freed of the inhibitory effects of Mdm2. This results in stabilization and activation of p53, leading to a multitude of biochemical and biological effects. The consequence of such p53 activation, when occurring in an incipient cancer cell, is the elimination of such cell from the replicative pool, preventing its further progression into a life-threatening tumor. The long term objective of this project is to elucidate the mechanisms responsible for maintaining p53 inactive in non-stressed cells, the biochemical events that enable p53 activation in response to cancer-related stress, and the molecular basis for the failure of p53 to function properly in human cancer cells, even when retained in its wild type form. Specifically, this work will address the impact of covalent modifications on Mdm2, particularly acetylation, evaluate the exact nature of the changes that are imposed on p53 as a consequence of Mdm2 activity, investigate the idea that some of the inhibitory effects of Mdm2 may involve its interaction with the chromatin of p53 target genes in a manner leading to transcriptional silencing, explore the possibility that dominant negative forms of p63, a p53 family member, are responsible for the failure of p53 to function as an effective tumor suppressor in some human cancers, and elucidate the regulation of p53 activation by cell-cell interaction and its relevance for the conversion of epithelial tumors to a more malignant state. The methodology will include a combination of cell-free assays for protein activity, mutational analysis and genetic manipulation of cultured cells, analysis of protein-protein interactions, gene expression analysis, and in vivo experiments in normal and cancer-bearing mice. Success of the proposed experiments should allow a better understanding of the regulation of p53 activity and its subversion in cancer, and provide clues for improved cancer therapy.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2012 ( Subtotal = $219,151 )
2012	2012	WEIZMANN INSTITUTE OF SCIENCE	POST OFFICE BOX 26	REHOVOTH				ISL	Cancer Biology Research	000	28	7/30/2012	NON-COMPETING CONTINUATION	$219,151
														Subtotal = $219,151

Issue Date FY: 2011 ( Subtotal = $225,725 )
2011	2011	WEIZMANN INSTITUTE OF SCIENCE	POST OFFICE BOX 26	REHOVOTH				ISL	Cancer Biology Research	000	27	6/9/2011	NON-COMPETING CONTINUATION	$225,725
														Subtotal = $225,725

Issue Date FY: 2010 ( Subtotal = $225,928 )
2010	2010	WEIZMANN INSTITUTE OF SCIENCE	POST OFFICE BOX 26	REHOVOTH				ISL	Cancer Biology Research	000	26	7/16/2010	NON-COMPETING CONTINUATION	$225,928
														Subtotal = $225,928

Issue Date FY: 2009 ( Subtotal = $221,499 )
2009	2009	WEIZMANN INSTITUTE OF SCIENCE	POST OFFICE BOX 26	REHOVOTH				ISL	Cancer Biology Research	000	25	7/8/2009	NON-COMPETING CONTINUATION	$221,499
														Subtotal = $221,499

Issue Date FY: 2008 ( Subtotal = $215,047 )
2008	2008	WEIZMANN INSTITUTE OF SCIENCE	POST OFFICE BOX 26	REHOVOTH		00000		ISR	Cancer Biology Research	000	24	9/4/2008	EXTENSION WITH OR WITHOUT FUNDS	$215,047
														Subtotal = $215,047

Issue Date FY: 2007 ( Subtotal = $204,049 )
2007	2007	WEIZMANN INSTITUTE OF SCIENCE	POST OFFICE BOX 26	REHOVOTH		00000		ISR	Cancer Biology Research	000	23	7/19/2007	NON-COMPETING CONTINUATION	$204,049
														Subtotal = $204,049

Issue Date FY: 2006 ( Subtotal = $210,143 )
2006	2006	WEIZMANN INSTITUTE OF SCIENCE	POST OFFICE BOX 26	REHOVOTH		00000		ISR	Cancer Biology Research	000	22	7/20/2006	NON-COMPETING CONTINUATION	$210,143
														Subtotal = $210,143

Issue Date FY: 2005 ( Subtotal = $215,200 )
2005	2005	WEIZMANN INSTITUTE OF SCIENCE	POST OFFICE BOX 26	REHOVOTH		00000		ISR	Cancer Biology Research	000	21	7/28/2005	NON-COMPETING CONTINUATION	$215,200
														Subtotal = $215,200

Issue Date FY: 2004 ( Subtotal = $215,200 )
2004	2004	WEIZMANN INSTITUTE OF SCIENCE	POST OFFICE BOX 26	REHOVOTH		00000		ISR	Cancer Biology Research	000	20	7/27/2004	NON-COMPETING CONTINUATION	$215,200
														Subtotal = $215,200

Issue Date FY: 2003 ( Subtotal = $215,200 )
2003	2003	WEIZMANN INSTITUTE OF SCIENCE	POST OFFICE BOX 26	REHOVOTH		00000		ISR	Cancer Biology Research	000	19	8/7/2003	COMPETING CONTINUATION	$215,200
														Subtotal = $215,200

Grand Total All Awards = $2,167,142

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FUNCTIONAL ANALYSIS OF THE P53 TUMOR SUPPRESSOR

Award Number: R37CA040099

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 08/15/1985

PERIOD OF PERFORMANCE END DATE: 07/30/2013

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