Lili Wang

Date of Award

Spring 2022

Document Type

Open Access Thesis

Department

Biomedical Science

First Advisor

Igor Roninson

Abstract

This project addresses the molecular and in vivo activities of transcriptionregulating module CKM, comprised of CDK8 (or CDK19) kinases, Cyclin C, MED12 and MED13. Our lab has found that CDK8/19 potentiates NFkB-induced transcription. In this study, we confirmed that both CDK8 and CDK19 regulate gene expression in kinasedependent manner. CDK8 and CDK19 are not required for NFkB-induced transcription, which also occurs in HEK293-dKO (CDK8 and CDK19 double knockout) cells, but such transcription becomes CDK8/19-dependent upon re-expression of CDK8 or CDK19 in dKO. Surprisingly. pre-treatment with a CDK8/19 inhibitor decreases the effect of CDK8/19 on NFkB-induced transcription.

In another set of studies, we found that CDK8 and CDK19 protect Cyclin C from proteasomal degradation in a kinase-independent manner. Cyclin C maintains its primarily nuclear localization in the absence of CDK8/19. The first human Cyclin C knockout derivative clones were developed in HEK293 cells. Cyclin C deficiency suppresses CDK8/19-regulated gene expression and it appears to suppress the cytoplasmic localization of MED12 protein of the CDK module.

Finally, we investigated the effects of CDK8/19 inhibition on metastatic spread after i.v. injection of tumor cells. In this setting, 22Rv1 castration-resistant prostate cancer (CRPC) metastasizes to various organs but not to the lungs; CDK8/19 inhibitor SNX631 had no apparent effect on the overall metastatic growth of 22Rv1 CRPC in intact male mice. In contrast, Abrams osteosarcoma selectively metastasizes to the lungs after i.v. injection. SNX631 was found to inhibit lung metastases causing their shrinkage over the long term and significantly extending the survival.

Rights

© 2022, Lili Wang

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