Date of Award

2022

Embargo Period

5-25-2022

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biochemistry

College

College of Graduate Studies

First Advisor

John Alan Diehl

Second Advisor

Robin Muise-Helmericks

Third Advisor

Phil Howe

Fourth Advisor

David Long

Fifth Advisor

Antonis Kourtidis

Abstract

Overexpression of c-myc via increased transcription or decreased protein degradation is common to many cancer etiologies. C-myc protein degradation is mediated by ubiquitin-dependent degradation and this ubiquitylation is regulated by several E3 ligases. The primary regulator is Fbxw7 which binds to a phospho-degron within c-myc. Here, we identify a new E3 ligase for c-myc, Fbxl8 (F-box and Leucine Rich Repeat Protein 8), as an adaptor component of the SCF (Skp1-Cullin1-F-box protein) ubiquitin ligase complex, for selective c-myc degradation. SCFFbxl8 binds and ubiquitylates c-myc, independent of phosphorylation revealing that it regulates a pool of c-myc distinct from SCFFbxw7. Reduction of Fbxl8 expression is correlated in 11 distinct tumor tissue types. Loss of Fbxl8 increases c-myc protein levels, protein stability, and cell division while overexpression of Fbxl8 reduces c-myc protein levels. Concurrent loss of Fbxl8 and Fbxw7 trigger a robust increase in c-myc protein levels consistent with targeting distinct pools of c-myc. This work highlights new mechanisms regulating c-myc degradation.

Rights

All rights reserved. Copyright is held by the author.

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