Elucidating Non-Canonical Interactions Of Mcl1 With The P53 Family Of Tumor Suppressors

Authors

Alexus Marie Acton, University of Alabama at Birmingham

Advisor(s)

William Placzek

Committee Member(s)

John Parant

Mythreye Karthikeyan

Natalia Kedishvilli

Nicholas Lennemann

Rui Lu

Document Type

Dissertation

Date of Award

1-1-2025

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Various signaling mechanisms contribute to a cancers cell’s ability to survive through the stressors of tumorigenesis. Canonically, when a cell is exposed to irreversible stress, the induction to apoptosis is regulated by the Bcl-2 family of apoptotic regulators. However, to accommodate for the stressors of tumor progression, many solid tumors over express one of the pro-survival proteins (e.g., BCL2, BCLxL, MCL1) allowing for persistent growth without the induction to cell death. Over the past 10 years, researchers have investigated how over expression of these pro-survival proteins contribute to chemoresistance to standard of care therapies. To sensitize cells to these apoptotic resistance mechanisms, BH3 mimetics have been developed to selectively target anti-apoptotic proteins in hopes to sensitize a variety of cancers to pro-apoptotic stimuli. This work highlights how the cross talk between the Bcl-2 family of apoptotic regulators impacts the tumor suppressor p53 family to control cell signaling mechanisms to modulate cell survival and migration. Here, we present how implementing a BH3 mimetic targeting MCL1 enhances p73 mediated cell death in response to cisplatin. Furthermore, we present a novel protein-protein interaction between the tumor suppressor p63 and MCL1. Finally, we show that MCL1 modulates PTBP1 activity, allowing MCL1 to modulate gene expression at the DNA and RNA levels to drive a pro-migratory phenotype in several solid tumor models. As the development of MCL1 targeted inhibitors continues to expand, this work will provide a foundation for how these inhibitors impact non-canonical signaling mechanisms of MCL1 outside of the canonical apoptotic pathway.

Comments

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Recommended Citation

Acton, Alexus Marie, "Elucidating Non-Canonical Interactions Of Mcl1 With The P53 Family Of Tumor Suppressors" (2025). All ETDs from UAB. 6816.
https://digitalcommons.library.uab.edu/etd-collection/6816