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Effects of hyperthermia and HSP70 protein overexpression on FOXO3a levels in Acute Lymphoblastic T-cells

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Title: Effects of hyperthermia and HSP70 protein overexpression on FOXO3a levels in Acute Lymphoblastic T-cells
Author: Verzijlenberg, Lisette
Department: Department of Molecular and Cellular Biology
Program: Molecular and Cellular Biology
Advisor: Mosser, Richard
Abstract: Cells that are damaged by hyperthermia are eliminated by apoptosis. Forkhead Box O3a (FoxO3a) is a transcription factor that triggers transcription of pro-apoptotic genes facilitating cell death. Normally FOXO3a associates with 14-3-3 proteins in the cytoplasm and is ubiquitinated and degraded by the proteasome. Turnover of FOXO3a is regulated by Akt-mediated phosphorylation at residues T32, S253, and S315. Dephosphorylation leads to nuclear translocation and transcriptional activation of the apoptotic program. Stress activates an evolutionarily conserved ‘heat shock response’ producing heat-shock proteins like HSP70, which act as a defence mechanism limiting protein damage and thereby allowing survival of cells exposed to proteotoxic stress. We demonstrated that hyperthermia causes nuclear translocation of FOXO3a which is inhibited in cells expressing HSP70. Additionally, hyperthermia targeted FOXO3a for proteasomal and caspase mediated degradation. Together, these results suggest a mechanism where HSP70 protects cells from cell stress by preventing the nuclear accumulation of FOXO3a and accelerating its destruction.
URI: http://hdl.handle.net/10214/11490
Date: 2017-08


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