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Novel functions of cell cycle proteins in G1/S phase progression and in cancer

Award Number: R01CA303628
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/13/2026
PERIOD OF PERFORMANCE END DATE: 07/31/2031

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Novel functions of cell cycle proteins in G1/S phase progression and in cancer - Project Summary/Abstract A complex composed of a regulatory protein, cyclin B, and its serine/threonine protein kinase partner, the cyclin-dependent kinase 1 (CDK1), was shown to play important, rate-limiting roles in driving entry of cells into and progression through mitosis by phosphorylating proteins that regulate nuclear envelope breakdown, chromosome condensation, mitotic spindle assembly and function, chromosome segregation and cytokinesis. In our recent study, we found that cyclin B-CDK1 kinase is also active in mammalian cells during late G1 phase. We observed that cyclin B-CDK1 cooperates with another protein kinase complex composed of a regulatory subunit, DBF4, and a catalytic subunit, cell division cycle 7-related protein kinase (CDC7), in regulating entry of cells into DNA synthesis (S) phase. The molecular role of cyclin B-CDK1 in G1/S phase progression is currently unknown. Therefore, in Aim 1 we will use mouse and human cells to identify the range of molecular functions played by cyclin B-CDK1 in G1/S cells. In Aim 2, we will study the molecular basis of the functional redundancy between cyclin B-CDK1 and DBF4-CDC7 in driving G1/S progression. This redundancy is revealed by the observation that inhibition of both cyclin B-CDK1 and DBF4-CDC7 is needed to arrest G1/S progression of mammalian cells. In Aim 3, we will study the impact of CDC7 inhibition on tumorigenesis using mice carrying patient-derived xenografts as well as mouse tumor models. Justification for the use of vertebrate animals. In Aim 3, we will be using vertebrate animals (mice): (i) immunocompromised mice will serve as recipients of patients’ tumors (patient-derived xenografts). Tumor-bearing mice will be treated with small-molecule CDC7 inhibitors and the impact on tumorigenesis will be assessed. Rationale: studying human tumors in vivo in the context of a living organism recapitulates tumorigenesis more closely than in vitro analyses. (ii) In addition, we will use genetically engineered mouse tumor models. These mice carry tumors with defined genetic lesions. Moreover, these mice will allow us to determine whether the effects of CDC7 inhibitors represent on-target effects. This is particularly important, as no highly selective small-molecule CDC7 inhibitor compounds are currently available. For these reasons, the experiments using mice are essential to establish the requirement for CDC7 function in tumor progression in vivo.


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 = $606,749 )
2026	2026	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Biology Research	000	1	8/13/2026	NEW	$606,749
														Subtotal = $606,749

Grand Total All Awards = $606,749

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Novel functions of cell cycle proteins in G1/S phase progression and in cancer

Award Number: R01CA303628

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/13/2026

PERIOD OF PERFORMANCE END DATE: 07/31/2031

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