Jiayuan Shi

Date of Award

8-2012

Level of Access Assigned by Author

Campus-Only Thesis

Degree Name

Master of Science (MS)

Department

Biochemistry

Advisor

Chengkai Dai

Second Committee Member

Mary Ann Handel

Third Committee Member

Rick Maser

Abstract

Protein homeostasis and genome integrity are critical for cells to maintain normal functions. Heat shock factor 1 (HSF1) and Ataxia telangiectasia mutated (ATM) are very important proteins involved in those processes. As a master regulator of heat shock response, HSF1 protects cell from proteotoxic stress by mediating the induction of heat shock protein. ATM, as a "caretaker gene", protects cells against DNA damage. Both of them are also involved in human cancer. Recent study has established that HSF1 is a potent modifier of tumorigenesis. Deficiency in ATM can cause increased cancer susceptibility in human A-T disease. However, whether and how HSF1 and its mediated stress response modify the oncogenesis in A-T remains completely unknown. In this study, we found that although basal HSF1 binding activity was enhanced, the heat shock-induced phosphorylation of HSF1 was decreased in ATM-deficient cells. Moreover, HSF1 transcriptional activity in both basal and heat shock condition was significantly decreased owing to loss of ATM kinase activity. The inhibition of HSF1 transcriptional activity by ATM deficiency resulted in a reduced level of heat shock protein induction during heat shock, increased accumulation of ubiquitinated protein and elevated sensitivity to proteotoxic stress. In mice, the level of heat shock protein was significantly reduced in the brain and tumor of Atm% mice. In conclusion, this study has shown that ATM deficiency impaired HSFl-mediated heat shock response. We also proposed several models that underlie the mechanism of this regulation.

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