Dissertation > Biological Sciences > Biochemistry > Protein

Phosphorylated-Hsp27Activates ATM-Dependent P53Signaling and Mediates Resistances of MCF-7Cells from Doxorubicin-Induced Apoptosis

Author XuYiMiao
Tutor YinZhiMin
School Nanjing Normal University
Course Biochemistry and Molecular Biology
Keywords cell survival heat shock protein27 cell cycle apoptosis signal transduction
Type PhD thesis
Year 2013
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As the target of tumor suppresser gene TP53, p53regulate both the apoptosis and DNA repair process. DNA damage activates p53target genes, which further lead to apoptosis or DNA repair process. In many tumor cells, the small heat shock protein Hsp27is expressed at a high level to provide protection against anticancer drugs. However, the roles of Hsp27in p53-mediated cellular responses to DNA damage are controversial.Here, we investigated the interplay between the phosphorylation status of Hsp27and p53in kidney293A (HEK293A) cells and found Hsp27can suppress p53mediated responses. Further we found Hsp27facilitated p53ubiquitnation while inhibiting MDM2transcription. Overall, Hsp27negatively regulated p53by facilitating its MDM2-dependent degradation while inhibiting some of p53downstream genes (eg., MDM2, p21) transcription.Hsp27can be phosphorylated within the cell. When over-expressing phosphorylated Hsp27mimics (Hsp27-3D), it activated p53/p21in ATM dependent manner. In line with these findings, human adenocarcinoma cells (MCF-7) incubation with a low dose of doxorubicin (Dox) also caused phosphorylation of Hsp27. Inhibition of Hsp27phosphorylation in Dox-treated MCF-7cells caused reduced p53induction and p21accumulation, which further increased cell apoptosis. Our results show that the phosphorylated Hsp27increases p53nuclear importing and some downstream gene expression while the un-phosphorylated Hsp27impedes this process. Taken together, our data suggest that Hsp27, in its phosphorylated or de-phosphorylated status, plays different roles in regulating p53pathway and cell survival.

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