Student Theses and Dissertations

Brian Hurwitz

Date of Award

2022

Document Type

Thesis

Degree Name

Doctor of Philosophy (PhD)

RU Laboratory

Fuchs Laboratory

Abstract

The integrated stress response (ISR) is a highly conserved pathway that senses diverse stresses and responds by limiting total protein synthesis and redirecting translation to stress response transcripts. The ISR has the potential to modify a broad range of processes in cancer, but the major cancer-relevant functions of the pathway have remained elusive due to the complex and redundant nature of the upstream kinases that sense stress and activate the pathway. To overcome this challenge, we genetically targeted the central, regulatory node of the pathway, eIF2α-serine 51, directly, in primary squamous cell carcinoma cells to generate "ISR-null" SCCs. We surprisingly found that the ISR acted as a tumor suppressor early in tumorigenesis, but also promoted proteostasis in response to the chemotherapy and proteasome inhibitor, bortezomib. We found this second finding to be mechanistically linked to a previously-undescribed role for the ISR in regulating the microtubule cytoskeleton to promote the removal of aggregated proteins. As a second goal of this project we sought to develop small molecule inhibitors of the ISR for anticancer therapy, focusing on the alternative translation initiation factor, EIF2A, which we previously found to be critical for oncogenesis. Utilizing dual luciferase reporters for alternative translation (Atf4-firefly) and housekeeping translation (HBB-renilla) we performed a high throughput screen and have identified promising hits with potential as novel EIF2A inhibitors.

Comments

A Thesis Presented to the Faculty of The Rockefeller University in Partial Fulfillment of the Requirements for the degree of Doctor of Philosophy

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