CSN-5: A TUMOR'S FRIEND OR FOE IN THE C. ELEGANS GERMLINE?

Author

Kellie C. Kuch, University of Montana, MissoulaFollow

Year of Award

2024

Document Type

Thesis

Degree Type

Master of Science (MS)

Degree Name

Biochemistry & Biophysics

Department or School/College

Biochemistry & Biophysics

Committee Chair

Dr. Travis Hughes

Commitee Members

Dr. Beverly Piggott, Dr. Erica Woodahl, Dr. Ekaterina Voronina

Keywords

CSN-5, C. elegans, germline, tumor, cancer

Subject Categories

Biochemistry | Biology | Genetics

Abstract

The COP9 signalosome is a highly conserved eukaryotic complex regulating protein degradation via deneddylation of Cullin-RING E3 ligases. CSN5, the COP9’s fifth component, contains the catalytically active domain for CSN deneddylation. The complex is inactive without CSN5; however, CSN5 engages in COP9-independent binding with several other proteins, typically promoting either destruction or stabilization of its partners. Many of its confirmed interaction partners are also implicated in tumorigenesis (prominent examples being p27 and p53) and a complex cancer interactome has been established for CSN5. Additionally, CSN5 overexpression has been documented in a staggering array of cancers of diverse origins. This discovery has led to the suggestion that its dysregulation may drive tumor formation and has increased interest in it for cancer therapeutics. However, while upregulation has been documented, it has not been confirmed whether tumorigenesis is indeed secondary to CSN5 overexpression. In this study, we use the germline of the well characterized model organism, C. elegans, to demonstrate that CSN-5 overexpression produces synthetic tumorigenesis as well as stem and progenitor cell population growth in select developmental contexts. Additionally, we establish CSN-5 as a conserved tumor biomarker across species and find that mutant csn-5 cannot prevent germline tumor formation, and in some cases increases it. Altogether, we suggest caution in pursuing CSN5 inhibition as a therapeutic without significant advances in understanding CSN5 mechanisms and regulation.

Recommended Citation

Kuch, Kellie C., "CSN-5: A TUMOR'S FRIEND OR FOE IN THE C. ELEGANS GERMLINE?" (2024). Graduate Student Theses, Dissertations, & Professional Papers. 12296.
https://scholarworks.umt.edu/etd/12296