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Biochemical Classification of Cancer Missense Mutations in the Retinoblastoma Protein

Award Number: SC3GM135037
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/05/2020
PERIOD OF PERFORMANCE END DATE: 03/31/2024

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Biochemical Classification of Cancer Missense Mutations in the Retinoblastoma Protein - Project Summary/Abstract The overall objective of this research is to characterize the structural mechanisms by which cancer mutations deregulate the retinoblastoma tumor suppressor protein (Rb). Rb is a multifunctional hub protein that facilitates protein-protein interactions in order to carry out various functions related to cell growth and chromatin regulation. Recent cancer genome sequencing data have highlighted sites of recurrent somatic and germline missense mutations, the majority of which occur to the highly-conserved pocket domain. A detailed molecular understanding of the direct structural and functional consequences of these mutations is key to parsing the mechanisms by which Rb deregulation occurs in cancers, as well as a first step toward identifying strategies to therapeutically restore loss of Rb function in cancer patients. The overall objective of this research will be achieved through two aims, which together will generate complete structure-function profiles for each of the 59 recurrent clinical missense mutations to the pocket domain of Rb. The goal of Aim 1 is to study Rb mutants as purified proteins in biochemical assays that characterize which protein-binding functions are perturbed by which mutations. To achieve this goal, a differential scanning fluorimetry (DSF) assay has been developed for use with Rb and protein interaction partners, which diagnoses changes to fold stability and protein-protein interactions that arise as a consequence of mutations. These assays will be further supported by data generated using fluorescence polarization (FP), isothermal titration calorimetry (ITC), and differential scanning calorimetry (DSC). Together, multiple biophysical parameters will be measured for each mutant; including, protein melting temperatures, Gibbs free energy of unfolding, and dissociation constants for multiple protein binding partners. The goal of Aim 2 is to reveal the structural basis of cancer mutations to Rb using protein x-ray crystallography. The hypothesis is that the mutations deregulate Rb through various structural mechanisms, including: the direct disruption of critical protein binding interfaces, negative allosteric regulation of protein binding interfaces, and overall changes to the stability of the pocket domain fold. A thorough understanding of the structural aspects underpinning the mechanisms by which mutations deregulate Rb will provide a solid basis for rational approaches to restore its function.


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: 2023 ( Subtotal = $110,250 )
2023	2023	UNIVERSITY ENTERPRISES CORPORATION AT CSUSB	5500 UNIVERSITY PKWY	SAN BERNARDINO	CA	92407	SAN BERNARDINO	USA	Biomedical Research and Research Training	000	4	3/16/2023	NON-COMPETING CONTINUATION	$110,250
														Subtotal = $110,250

Issue Date FY: 2022 ( Subtotal = $110,250 )
2022	2022	UNIVERSITY ENTERPRISES CORPORATION AT CSUSB	5500 UNIVERSITY PKWY	SAN BERNARDINO	CA	92407	SAN BERNARDINO	USA	Biomedical Research and Research Training	001	3	6/20/2022	NON-COMPETING CONTINUATION	$11,025
2022	2022	UNIVERSITY ENTERPRISES CORPORATION AT CSUSB	5500 UNIVERSITY PKWY	SAN BERNARDINO	CA	92407	SAN BERNARDINO	USA	Biomedical Research and Research Training	000	3	3/25/2022	NON-COMPETING CONTINUATION	$99,225
														Subtotal = $110,250

Issue Date FY: 2021 ( Subtotal = $110,250 )
2021	2021	UNIVERSITY ENTERPRISES CORPORATION AT CSUSB	5500 UNIVERSITY PKWY	SAN BERNARDINO	CA	92407	SAN BERNARDINO	USA	Biomedical Research and Research Training	000	2	3/24/2021	NON-COMPETING CONTINUATION	$110,250
														Subtotal = $110,250

Issue Date FY: 2020 ( Subtotal = $110,250 )
2020	2020	UNIVERSITY ENTERPRISES CORPORATION AT CSUSB	5500 UNIVERSITY PKWY	SAN BERNARDINO	CA	92407	SAN BERNARDINO	USA	Biomedical Research and Research Training	000	1	5/5/2020	NEW	$110,250
														Subtotal = $110,250

Grand Total All Awards = $441,000

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Biochemical Classification of Cancer Missense Mutations in the Retinoblastoma Protein

Award Number: SC3GM135037

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/05/2020

PERIOD OF PERFORMANCE END DATE: 03/31/2024

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