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Cyclin C-CDK8/19 kinases in development and in cancer

Award Number: R01CA269285
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/01/2022
PERIOD OF PERFORMANCE END DATE: 02/28/2027

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Cyclin C-CDK8/19 kinases in development and in cancer - Project Summary/Abstract Cyclin C was cloned, along with other G1 cyclins, as a cDNA which can rescue the proliferative block in yeast Saccharomyces cerevisiae lacking CLN1, CLN2 and CLN3 genes. Subsequent work revealed that cyclin C, acting together with its kinase partners, the cyclin-dependent kinase 8 (CDK8) and CDK19, plays a role in regulating gene transcription. Cyclin C serves as a regulatory partner of CDK8 and CDK19, and activates the kinase activity of these proteins. The two paralog kinases show substantial overall amino acid identity, particularly within their catalytic domains. Cyclin C, CDK8 and CDK19 represent parts of the mediator complex, a large multisubunit protein complex that regulates gene transcription by linking RNA polymerase II to sequence-specific transcription factors. In addition, cyclin C-CDK8/19 was shown to phosphorylate various transcription factors and to regulate their stability and activity. Growing evidence indicates that cyclin C-CDK8 and C-CDK19 kinases may represent potential anti-cancer targets. CDK8 has been identified as an oncogene in several human cancers. Cyclin C, CDK8 and CDK19 are overexpressed in a wide range of tumor types. Importantly, higher expression of these three proteins was found to be associated with poor clinical outcome. Consistent with tumor-promoting roles for cyclin C-CDK8/19, treatment of mice bearing xenografts of several human tumor types with small molecule CDK8/19 inhibitors resulted in a potent anti-tumor effect without apparent systemic toxicity. To understand the molecular function of cyclin C in vivo, we generated conditional cyclin C knockout mice (cyclin CF/F). To test the impact of cyclin C-CDK8/19 inhibition on T cell development and adaptive anti-tumor immunity, we crossed cyclin CF/F mice with CD4-Cre animals. The latter strain expresses Cre recombinase at an early stage of T cell development, and drives deletion of the ‘floxed’ sequences in all T cell subsets. In our preliminary analyses we established that cyclin C functions as a gate- keeper of T cell differentiation, likely by directly phosphorylating a lineage-specific transcription factor. By doing so, cyclin C affects signaling networks that regulate the immune response. Hence, this novel function of cyclin C may have a profound effect on the anti-tumor immune response and on tumorigenesis. In the proposed work we will extend these studies. In Aim 1, we will study the exact molecular function of cyclin C- CDK8 and C-CDK19 in the T cell lineage using a combination of biochemical in vitro studies, cell culture experiments, analyses of ex vivo cultured T cells as well as mouse genetic approaches. In Aim 2, we will study how ablation of cyclin C impacts tumorigenesis in vivo, using mouse cancer models and combination treatments with other anti-cancer modalities. In Aim 3, we will extend these cancer studies to cyclin C catalytic partners, using conditional Cdk19 knockout mice (Cdk19F/F), that my laboratory generated for this purpose. The expected overall impact of this proposal is that it will reveal a novel and important function of cyclin C- CDK8 and C-CDK19 in tumorigenesis, and will validate these kinases as attractive therapeutic targets.


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 = $525,969 )
2026	2026	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Treatment Research	000	5	4/17/2026	NON-COMPETING CONTINUATION	$525,969
														Subtotal = $525,969

Issue Date FY: 2025 ( Subtotal = $525,969 )
2025	2025	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Treatment Research	001	4	5/28/2025	NON-COMPETING CONTINUATION	$52,596
2025	2025	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Treatment Research	000	4	3/4/2025	NON-COMPETING CONTINUATION	$473,373
														Subtotal = $525,969

Issue Date FY: 2024 ( Subtotal = $499,671 )
2024	2024	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Treatment Research	001	3	4/24/2024	NON-COMPETING CONTINUATION	$26,298
2024	2024	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Treatment Research	000	3	4/1/2024	NON-COMPETING CONTINUATION	$473,373
														Subtotal = $499,671

Issue Date FY: 2023 ( Subtotal = $515,451 )
2023	2023	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Treatment Research	000	2	2/28/2023	NON-COMPETING CONTINUATION	$515,451
														Subtotal = $515,451

Issue Date FY: 2022 ( Subtotal = $525,969 )
2022	2022	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Treatment Research	000	1	2/24/2022	NEW	$525,969
														Subtotal = $525,969

Grand Total All Awards = $2,593,029

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Cyclin C-CDK8/19 kinases in development and in cancer

Award Number: R01CA269285

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/01/2022

PERIOD OF PERFORMANCE END DATE: 02/28/2027

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