All ETDs from UAB

Advisory Committee Chair

William J Placzek

Advisory Committee Members

Mary-Ann Bjornsti

David M Bedwell

Chad M Petit

Rui Zhao

Document Type

Dissertation

Date of Award

2018

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Apoptosis, a highly regulated process of programmed cell death, is essential for maintaining normal tissue homeostasis. Myeloid cell leukemia 1 (MCL1), an anti-apoptotic BCL-2 family protein, lies at the center of apoptosis regulation. Overexpression of MCL1 has been identified as a key contributor to tumorigenesis and further enables resistance to anti-cancer chemotherapies and radiation. Due to the critical roles of MCL1 in cancer, it is essential to understand the regulatory mechanisms of MCL1 expression in cells. Previous studies have detailed how MCL1 expression is controlled by multiple mechanisms. However, characterization of the post-transcriptional regulation of MCL1 mRNA has been poorly studied. Polypyrimidine tract binding protein 1 (PTBP1) is an RNA binding protein that is known to regulate gene expression post-transcriptionally via its control over RNA. Here we identify PTBP1 as a novel MCL1 repressor that binds to and destabilizes MCL1 mRNA. Additionally, we show that PTBP1 silencing protects cancer cells from antitubulin agent-induced apoptosis in a MCL1-dependent manner. We further characterize the corresponding mechanisms by which PTBP1 modulates MCL1 expression via regulating microRNA (miRNA)-direction of the miRNA induced silencing complex (miRISC) to MCL1. We demonstrate that PTBP1 enhances miR-101-guided AGO2 interaction with MCL1, thereby facilitating miR-101’s inhibition in cell survival. In summary, our studies extensively characterize the PTBP1-mediated post-transcriptional control of MCL1 in cancer and open up the field to further investigate the RNA binding protein-miRNA network in regulating MCL1 and MCL1-controlled apoptosis under normal development and disease conditions.

Share

COinS