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UV AND P21 DEGRADATION

Award Number: R01CA108947
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/15/2005
PERIOD OF PERFORMANCE END DATE: 04/30/2010

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UV AND P21 DEGRADATION - DESCRIPTION (provided by applicant): p21WAF1/CIP1 is a transcriptional target of the tumor suppressor p53. p21 protein plays an essential role in cell cycle arrest after ionizing radiation, in certain forms of cancer, autoimmunity and stem cell repopulation. Although pathways that converge on p21 gene transcription are well studied, here we examine the mechanisms that regulate p21 protein stability and their effect on p21 function. In preliminary results we show that UV induces p21 degradation. We show that while low doses of UV induce p21 degradation high doses do not. The ability of UV to induce p21 degradation is dependent on ubiquitin and the F box protein Skp2. Our results show that the cell cycle arrest by UV is p21 independent in contrast to the classical p21 dependent arrest by ionizing radiation. Finally we show that failure to degrade p21 after UV irradiation inhibits both the recruitment of PCNA to chromatin and DMA repair synthesis. In this proposal we will study three aspects of the mammalian cellular response to UV and the critical role p21 plays in this process. First, we will identify the signaling proteins downstream of ATR which induce p21 degradation after low doses of UV. Second, we will identify the kinase which phosphorylates p21 and the phosphorylation site in p21 which dictates Skp2 / p21 binding after UV. We will also examine if Skp2 dependent UV induced p21 degradation is also dependent on Cks1 and allow us to reconstitute UV induced p21 ubiquitination in vitro. Third, we will generate whole animal models in which cellular p21 cannot be ubiquitinated and determine the biological consequences of such a mutation. This will include the effect on cell cycle, checkpoint signaling and skin cancer.


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: 2009 ( Subtotal = $322,426 )
2009	2009	SIDNEY KIMMEL CANCER CENTER	10905 Road To The Cure	San Diego	CA	92121	SAN DIEGO	USA	Cancer Cause and Prevention Research	001	5	8/11/2009	NON-COMPETING CONTINUATION	-$272,725
2009	2009	BURNHAM INSTITUTE FOR MEDICAL RESEARCH	10901 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Cancer Cause and Prevention Research	002	6	8/12/2009	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$269,870
2009	2009	SIDNEY KIMMEL CANCER CENTER	10905 Road To The Cure	San Diego	CA	92121	SAN DIEGO	USA	Cancer Cause and Prevention Research	000	5	3/31/2009	NON-COMPETING CONTINUATION	$325,281
														Subtotal = $322,426

Issue Date FY: 2008 ( Subtotal = $325,281 )
2008	2008	SIDNEY KIMMEL CANCER CENTER	10835 ALTMAN ROW	SAN DIEGO	CA	92121	SAN DIEGO	USA	Cancer Cause and Prevention Research	000	4	4/23/2008	NON-COMPETING CONTINUATION	$325,281
														Subtotal = $325,281

Issue Date FY: 2007 ( Subtotal = $325,281 )
2007	2007	SIDNEY KIMMEL CANCER CENTER	10835 ALTMAN ROW	SAN DIEGO	CA	92121	SAN DIEGO	USA	Cancer Cause and Prevention Research	000	3	4/19/2007	NON-COMPETING CONTINUATION	$325,281
														Subtotal = $325,281

Issue Date FY: 2006 ( Subtotal = $334,996 )
2006	2006	SIDNEY KIMMEL CANCER CENTER	10835 ALTMAN ROW	SAN DIEGO	CA	92121	SAN DIEGO	USA	Cancer Cause and Prevention Research	000	2	6/14/2006	NON-COMPETING CONTINUATION	$334,996
														Subtotal = $334,996

Issue Date FY: 2005 ( Subtotal = $344,243 )
2005	2005	SIDNEY KIMMEL CANCER CENTER	10835 ALTMAN ROW	SAN DIEGO	CA	92121	SAN DIEGO	USA	Cancer Cause and Prevention Research	000	1	6/15/2005	NEW	$344,243
														Subtotal = $344,243

Grand Total All Awards = $1,652,227

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UV AND P21 DEGRADATION

Award Number: R01CA108947

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/15/2005

PERIOD OF PERFORMANCE END DATE: 04/30/2010

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