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Functions and Activities of p53 and Mdm2 in Normal and Cancer Cells

Award Number: R35CA220526
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/17/2018
PERIOD OF PERFORMANCE END DATE: 07/31/2025

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Functions and Activities of p53 and Mdm2 in Normal and Cancer Cells - Functions and Activities of p53 and Mdm2 in Normal and Cancer Cells. The p53 protein, a major suppressor of cancer in animals and humans, is a DNA sequence specific regulator of transcription of hundreds of genes whose products mediate cellular outcomes such as cell cycle arrest, cell death, senescence, metabolic changes, DNA repair and others that are consistent with tumor suppression. While a potent regulator of such processes in cells undergoing various forms of genotoxic or oncogenic stress, if allowed to function unchecked, p53 can be damaging or even lethal to cells and tissues. Keeping p53 under tight control is therefore as important as allowing it to function when needed. The two proteins that play the most central role in suppressing p53 are Mdm2 and its homologue MdmX. Over half of all human malignancies (depending on the tumor type) harbor wild-type p53, which if released from Mdm2/X, might be effective as a cytostatic or cytotoxic anti-tumor agent. Yet reagents (peptides and small molecules) that prevent Mdm2 from binding to p53 have not yet been fully realized as effective therapeutic agents. Similarly, there few effective drugs in the clinic that prevent the oncogenic activities of mutant p53. Further, increasing lines of evidence document p53-independent roles of Mdm2 and MdmX in cancer cells that can be exploited for therapeutic and diagnostic purposes. The work proposed in this application for an Outstanding Investigator Award follows a long history of contributions in the laboratory of the PI to our understanding p53, Mdm2 and MdmX that continue to the present day. The plans going forward build on new findings in the PI's lab, and incorporate novel technologies in order to gain more global and mechanistic information about the p53/Mdm axis. The research proposed will extend recent discoveries related to (i) a novel mechanism by which Mdm2 degrades p53 and the possibility that this finding can lead to new therapeutics that prevent Mdm2 degradation of wild-type p53 or conversely facilitate Mdm2 degradation of oncogenic mutant forms of p53, (ii) a series of CRISPR-derived cell lines harboring unique Li-Fraumeni-Syndrome p53 mutations; (iii) p53- independent roles of Mdm2 and MdmX that may either prevent or support oncogenesis, (iv) long non-coding RNAs that are p53 targets and which may provide new biomarkers in human cancers; (v) new approaches to understand how p53 identifies its sites in vitro and in vivo and, (vi) examination at single molecule resolution the localization of wild-type and mutant forms of p53 and Mdm2 after different stimuli. The long term goals of this program will hopefully lead to new tools for diagnosis and treatment of sporadic and inherited cancers.


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: 2026 ( Subtotal = -$856 )
2026	2024	THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	615 W 131ST ST	NEW YORK	NY	10027	NEW YORK	USA	Cancer Biology Research	000	7	12/9/2025	NON-COMPETING CONTINUATION	-$856
														Subtotal = -$856

Issue Date FY: 2024 ( Subtotal = $812,976 )
2024	2024	THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	615 W 131ST ST	NEW YORK	NY	10027	NEW YORK	USA	Cancer Biology Research	000	7	7/25/2024	NON-COMPETING CONTINUATION	$812,976
														Subtotal = $812,976

Issue Date FY: 2023 ( Subtotal = $855,901 )
2023	2023	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	202 LOW LIBRARY 535 W 116 ST MC 4309,	NEW YORK	NY	10027	NEW YORK	USA	Cancer Biology Research	000	6	8/1/2023	NON-COMPETING CONTINUATION	$855,901
														Subtotal = $855,901

Issue Date FY: 2022 ( Subtotal = $855,902 )
2022	2022	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	202 LOW LIBRARY 535 W 116 ST MC 4309,	NEW YORK	NY	10027	NEW YORK	USA	Cancer Biology Research	000	5	7/1/2022	NON-COMPETING CONTINUATION	$855,902
														Subtotal = $855,902

Issue Date FY: 2021 ( Subtotal = $870,147 )
2021	2021	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	116TH AND BDWY	NEW YORK	NY	10027	NEW YORK	USA	Cancer Biology Research	000	4	6/24/2021	NON-COMPETING CONTINUATION	$870,147
														Subtotal = $870,147

Issue Date FY: 2020 ( Subtotal = $840,979 )
2020	2020	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	116TH AND BDWY	NEW YORK	NY	10027	NEW YORK	USA	Cancer Biology Research	000	3	7/16/2020	NON-COMPETING CONTINUATION	$840,979
														Subtotal = $840,979

Issue Date FY: 2019 ( Subtotal = $847,168 )
2019	2019	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	116TH AND BDWY	NEW YORK	NY	10027	NEW YORK	USA	Cancer Biology Research	000	2	8/1/2019	NON-COMPETING CONTINUATION	$847,168
														Subtotal = $847,168

Issue Date FY: 2018 ( Subtotal = $873,370 )
2018	2018	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	116TH AND BDWY	NEW YORK	NY	10027	NEW YORK	USA	Cancer Biology Research	000	1	8/17/2018	NEW	$873,370
														Subtotal = $873,370

Grand Total All Awards = $5,955,587

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Functions and Activities of p53 and Mdm2 in Normal and Cancer Cells

Award Number: R35CA220526

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/17/2018

PERIOD OF PERFORMANCE END DATE: 07/31/2025

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