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Understanding interplay between the Hsp70 chaperone code and Cyclin D1/Cln3

Award Number: R03CA289058
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2025
PERIOD OF PERFORMANCE END DATE: 08/31/2027

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Understanding interplay between the Hsp70 chaperone code and Cyclin D1/Cln3 - Project Summary Hsp70 is vital molecular chaperone that folds a large proportion of the proteome. Research has primarily focused on how Hsp70 function specificity arises through regulation of a) expression of Hsp70, b) isoform differences in the Hsp70 protein family and c) the variety of co-chaperone proteins that bind to the Hsp70 molecule. Despite the identification of several phosphorylation sites on both yeast and mammalian Hsp70 through global proteomic screens, the biological function of most of these sites remains unknown. All organisms require correct coordination of the cell cycle to grow and proliferate. Uncontrolled cell cycle progression can result in either cell death or metastasis. Progression of the cell from G1 to G2 requires the activity of cyclin-dependent kinase (CDK) CDK4. The critical activity of CDK4 is regulated by binding to cyclin proteins such as Cyclin D1, which rises and falls in abundance periodically through the cell cycle. As such, altered Cyclin D1 activity (achieved through increased transcription or stability) is often correlated with tumorigenesis. Any strategy that lowers Cyclin D1 activity in cells may form the basis of novel anticancer therapies. Our studies have determined that phosphorylation of a single site on Hsp70 regulates chaperone function by altering both co-chaperone and client protein interactions. In particular, we have shown that increased Hsp70 T38 phosphorylation promotes Cyclin D1 destruction. In this proposal, we will investigate the role of other Hsp70 PTMs (the chaperone code) on Cyclin D1 levels in yeast and mammalian cells using the chaperone code array. We propose to use cross-linking mass spectrometry to fully characterize the Hsp70-Cyclin D1/Cln3 interaction, including binding surfaces and PTMs involved. The scope of this work has broad implications for a variety of diseases associated with both the cell cycle and molecular chaperone function, including many types of cancer and neurodegenerative illnesses.


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: 2025 ( Subtotal = $150,784 )
2025	2025	UNIVERSITY OF NORTH CAROLINA AT CHARLOTTE	9201 UNIVERSITY CITY BLVD	CHARLOTTE	NC	28223	MECKLENBURG	USA	Cancer Biology Research	000	1	8/22/2025	NEW	$150,784
														Subtotal = $150,784

Grand Total All Awards = $150,784

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Understanding interplay between the Hsp70 chaperone code and Cyclin D1/Cln3

Award Number: R03CA289058

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2025

PERIOD OF PERFORMANCE END DATE: 08/31/2027

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