Graduation Date

Fall 12-20-2019

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Genetics, Cell Biology & Anatomy

First Advisor

Dr. Vimla Band

Abstract

The hallmarks of cancer include sustained proliferation and survival in the face of cellular stresses imposed by the oncogenic drive, as well as metabolic rewiring for tumor growth under adverse nutritional conditions. Adaptive alterations in key biochemical networks that underlie metabolic rewiring represent potential opportunities to develop new therapeutic strategies against cancer.

My thesis focuses on mammalian Ecdysoneless (ECD), a conserved homolog of the fly Ecdysoneless gene product, which engages fundamental cell biological processes of ER stress, Ca2+ signaling and metabolism to help sustain the oncogenic drive in tumor cells. Recent studies from our laboratory provide a clear evidence that ECD is essential for cell cycle progression and cellular stress mitigation, and that ECD overexpression has a pro-oncogenic role in cancer.

In my thesis, we present evidence that ECD regulates store operated Ca2+ entry to maintain ER homeostasis by directly binding to ER Ca2+ sensor protein, STIM1, stabilizing it and regulating its function.

Moreover, we found ECD transcription increases during ER stress conditions, such as hypoxia through the stress sensor-transcription factor, OCT1, which binds to ECD promoter and regulates its transcription. In addition, ECD regulates mRNA levels of hypoxia inducing transcription factor, HIF1α. Finally, we show ECD levels regulate glucose uptake in a cell. Taken together, we present evidence that ECD via regulating SOCE-HIF1α-metabolism pathway provides survival advantage to the cell under ER stress conditions. Given the overexpression of ECD in several cancers, our studies have established a new mechanistic paradigm of how tumor cell hyper-proliferation and cell survival is driven by a novel mechanism that can be potentially targeted for therapy.

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