All ETDs from UAB

Advisory Committee Chair

William J Placzek

Advisory Committee Members

Douglas Hurst

Natalia Kedishvili

John Parant

Lalita Shevde-Samant

Document Type

Dissertation

Date of Award

2021

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

The determination of cell fate is a dynamic process regulated by hundreds of proteins that converge into complex cell signaling pathways. Upon irreparable intracellular stress, a cell undergoes programmed cell death, a process known as intrinsic apoptosis. Apoptosis is regulated by the Bcl-2 family, a class of proteins that act either as pro-survival or pro-death signaling molecules. Due to the oncogenic upregulation of pro- survival Bcl-2 family proteins across human cancer cell types, a novel class of small molecule inhibitors called ‘BH3-mimetics’ have emerged as promising anti-cancer therapeutics currently under clinical investigation. Here, we highlight the crosstalk between anti-apoptotic Bcl-2 family member, MCL1, and how it interacts with complex cellular circuits to modulate cell survival. Furthermore, we present a novel protein- protein interaction between MCL1 and tumor suppressor p73, characterizing a novel role of MCL1 in modulating transcriptional regulation. Importantly, there is significant crosstalk between MCL1 and the DNA damage response pathway that extends beyond p73 regulation, providing an opportunity for targeted combination therapy with emerging MCL1 inhibitors. As we transition into an era of Precision Medicine, this work will provide a foundation for applying MCL1 inhibitors to current standard of care in combination with cytotoxic therapy, radiation therapy, or other targeted therapeutics.

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