Date Approved

1-29-2024

Embargo Period

1-29-2024

Document Type

Dissertation

Degree Name

Doctor of Philosophy (Ph.D.)

Department

Molecular Biology

College

Rowan-Virtua School of Translational Biomedical Engineering & Sciences

Advisor

Randy Strich, Ph.D.

Committee Member 1

Dimitri Pestov, Ph.D.

Committee Member 2

Brian Weiser, Ph.D.

Committee Member 3

James Holaska, Ph.D.

Committee Member 4

Kerry Campbell, Ph.D.

Keywords

Cancer, CKM, cyclin C, Proteasome, Proteostasis, Transcription

Subject(s)

Carcinogenesis

Disciplines

Biochemistry, Biophysics, and Structural Biology | Life Sciences | Molecular Biology

Abstract

The underlying etiology of numerous disease states results from perturbations in the maintenance of cellular proteostasis. Carcinogenesis relies on these perturbations to foster uncontrolled cell growth and eventual metastases, while neurodegenerative diseases are a consequence of such perturbations. Control of these processes occurs at numerous molecular levels, commonly starting with transcription. A key transcriptional complex that is involved is the CDK8 Kinase Module (CKM). The CKM is conserved from yeast to man, forming a tetrameric complex consisting of MED12, MED13, CDK8, and CCNC. The CKM has not only been implicated in a variety of cancers but also in a spectrum of developmental disorders. Using RNA sequencing on murine and human cell lines, I showed that the CKM regulates the transcription of genes mediating conserved proteostasis pathways including translation, protein degradation, and differentiation. In addition, I showed that these processes are druggable targets, as chemotherapeutics aimed at translation and protein degradation, sensitized CCNC-/- cells to cell death. The use of CKM inhibitors phenocopied this sensitivity when cyclin C was present. As customized drug treatments become a reality, these data represent an approach that may be used to target cancers. These data further present a model of how mutations in the CKM can contribute to a diverse spectrum of disease states.

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