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Allosteric Regulation of MDMX by Protein Disorder

Award Number: R01CA141244
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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MDMX and MDM2 are homologues that regulate the p53 tumor suppressor using different mechanisms. While MDM2 is responsible for controlling p53 degradation, MDMX regulates p53 DNA binding and transcriptional activities. MDMX overexpression occurs in a subset of human tumors leading to inactivation of p53. Efficient p53 response to stress and DNA damage involves phosphorylation of MDMX followed by release of p53. Successful targeting of the p53 pathway for cancer therapy requires understanding how MDMX regulates p53 function. MDMX contains an ordered p53 binding domain and RING domain, and two long disordered regions that regulate p53 and CK1a binding in a phosphorylation- dependent manner. Our work identified intra- and intermolecular interactions essential for MDMX functions: (1) MDMX/p53 interaction inhibits p53 DNA binding. (2) MDMX/MDM2 interaction promotes MDMX degradation. (3) MDMX/14-3-3 interaction promotes MDMX nuclear translocation. (4) MDMX/CK1a interaction promotes MDMX/p53 binding and inhibition of p53. (5) MDMX intramolecular interaction regulates p53 binding. Importantly, these interactions are regulated by two phosphorylation sites (S289, S367) located in intrinsically disordered regions (IDR) of MDMX. We hypothesize that the coordinated control is mediated by intramolecular interactions between ordered and disordered regions of MDMX. The IDRs regulate the switching of intra/inter-molecular contacts in a phosphorylation-dependent manner. We propose integrated molecular biology and biophysics approach to elucidate the mechanism of MDMX regulation: (1) Determine how the length and flexibility of MDMX IDR1 regulates auto- inhibition of p53 binding. (2) Investigate how CK1a phosphorylation switches MDMX to an open conformation that inhibits p53 DNA binding. (3) Determine how Chk2 phosphorylation of IDR2 S367 regulates multiple MDMX interactions. These experiments will significantly advance the understanding of how stress signals activate p53 by targeting disordered regions of MDMX, which is essential to develop MDMX inhibitors for 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: 2024 ( Subtotal = $321,415 )
2024	2024	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Biology Research	000	13	12/19/2023	NON-COMPETING CONTINUATION	$304,497
2024	2024	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 USF MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Biology Research	001	13	4/17/2024	NON-COMPETING CONTINUATION	$16,918
														Subtotal = $321,415

Issue Date FY: 2023 ( Subtotal = $338,330 )
2023	2023	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Biology Research	000	12	12/19/2022	NON-COMPETING CONTINUATION	$304,497
2023	2023	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Biology Research	001	12	3/15/2023	NON-COMPETING CONTINUATION	$33,833
														Subtotal = $338,330

Issue Date FY: 2022 ( Subtotal = $382,811 )
2022	2022	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Biology Research	002	11	8/15/2022	COMPETING CONTINUATION	$27,356
2022	2022	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Biology Research	001	11	4/18/2022	COMPETING CONTINUATION	-$85,373
2022	2022	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Biology Research	000	11	12/31/2021	COMPETING CONTINUATION	$440,828
														Subtotal = $382,811

Issue Date FY: 2021 ( Subtotal = -$13,013 )
2021	2019	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Biology Research	000	10	7/27/2021	NON-COMPETING CONTINUATION	-$13,013
														Subtotal = -$13,013

Issue Date FY: 2019 ( Subtotal = $365,293 )
2019	2019	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Biology Research	000	10	2/1/2019	NON-COMPETING CONTINUATION	$365,293
														Subtotal = $365,293

Issue Date FY: 2018 ( Subtotal = $376,591 )
2018	2018	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Biology Research	001	9	5/23/2018	NON-COMPETING CONTINUATION	$37,660
2018	2018	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Biology Research	000	9	2/16/2018	NON-COMPETING CONTINUATION	$338,931
														Subtotal = $376,591

Issue Date FY: 2017 ( Subtotal = $376,591 )
2017	2017	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Biology Research	000	8	2/17/2017	NON-COMPETING CONTINUATION	$338,932
2017	2017	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Biology Research	001	8	6/7/2017	NON-COMPETING CONTINUATION	$37,659
														Subtotal = $376,591

Issue Date FY: 2016 ( Subtotal = $370,336 )
2016	2016	H LEE MOFFITT CANCER CENTER & RESEARCH INSTITUTE	12902 MAGNOLIA DRIVE	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Biology Research	000	7	2/4/2016	NON-COMPETING CONTINUATION	$370,336
														Subtotal = $370,336

Issue Date FY: 2015 ( Subtotal = $387,461 )
2015	2015	H LEE MOFFITT CANCER CENTER & RESEARCH INSTITUTE	12902 MAGNOLIA DRIVE	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Biology Research	001	6	12/24/2014	COMPETING CONTINUATION	$387,461
2015	2013	H LEE MOFFITT CANCER CENTER & RESEARCH INSTITUTE	12902 MAGNOLIA DRIVE	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Cause and Prevention Research	000	5	12/19/2014	NON-COMPETING CONTINUATION	$0
														Subtotal = $387,461

Issue Date FY: 2013 ( Subtotal = $315,962 )
2013	2013	H LEE MOFFITT CANCER CENTER & RESEARCH INSTITUTE	12902 MAGNOLIA DRIVE	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Cause and Prevention Research	000	5	5/1/2013	NON-COMPETING CONTINUATION	$78,991
2013	2013	H LEE MOFFITT CANCER CENTER & RESEARCH INSTITUTE	12902 MAGNOLIA DRIVE	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Cause and Prevention Research	001	5	7/1/2013	NON-COMPETING CONTINUATION	$236,971
														Subtotal = $315,962

Issue Date FY: 2012 ( Subtotal = $336,129 )
2012	2012	H LEE MOFFITT CANCER CENTER & RESEARCH INSTITUTE	12902 MAGNOLIA DRIVE	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Cause and Prevention Research	001	4	4/16/2012	NON-COMPETING CONTINUATION	$336,129
2012	2011	H LEE MOFFITT CANCER CENTER & RESEARCH INSTITUTE	12902 MAGNOLIA DRIVE	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Cause and Prevention Research	000	3	1/9/2012	NON-COMPETING CONTINUATION	$0
														Subtotal = $336,129

Issue Date FY: 2011 ( Subtotal = $336,129 )
2011	2011	H LEE MOFFITT CANCER CENTER & RESEARCH INSTITUTE	12902 MAGNOLIA DRIVE	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Cause and Prevention Research	001	3	5/13/2011	NON-COMPETING CONTINUATION	$24,256
2011	2011	H LEE MOFFITT CANCER CENTER & RESEARCH INSTITUTE	12902 MAGNOLIA DRIVE	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Cause and Prevention Research	000	3	3/8/2011	NON-COMPETING CONTINUATION	$311,873
														Subtotal = $336,129

Issue Date FY: 2010 ( Subtotal = $346,525 )
2010	2010	H LEE MOFFITT CANCER CENTER & RESEARCH INSTITUTE	12902 MAGNOLIA DRIVE	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Cause and Prevention Research	000	2	4/22/2010	NON-COMPETING CONTINUATION	$346,525
														Subtotal = $346,525

Issue Date FY: 2009 ( Subtotal = $346,525 )
2009	2009	H LEE MOFFITT CANCER CENTER & RESEARCH INSTITUTE	12902 MAGNOLIA DRIVE	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Cause and Prevention Research	000	1	6/17/2009	NEW	$346,525
														Subtotal = $346,525

Grand Total All Awards = $4,587,085

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Allosteric Regulation of MDMX by Protein Disorder

Award Number: R01CA141244

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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