Phosphorylated Hsp27 activates ATM-dependent p53 signaling and mediates the resistance of MCF-7 cells to doxorubicin-induced apoptosis.

Abstract

DNA damage activates p53 and its downstream target genes, which further leads to apoptosis or survival either by the cell cycle arrest or by DNA repair. In many tumors, the heat shock protein 27 (Hsp27) is expressed at high levels to provide protection against anticancer drugs. However, the roles of Hsp27 in p53-mediated cellular responses to DNA damage are controversial. Here, we investigated the interplay between the phosphorylation status of Hsp27 and p53 in kidney 293A (HEK293A) cells and found that over-expressing phosphorylated Hsp27 mimics (Hsp27-3D) activated p53/p21 in an ATM-dependent manner. In addition, incubation with doxorubicin (Dox), an anticancer drug, induced Hsp27 phosphorylation in human adenocarcinoma cells (MCF-7). In contrast, inhibition of Hsp27 phosphorylation retarded both p53 induction and p21 accumulation, and led to cell apoptosis. Furthermore, phosphorylated Hsp27 increased p53 nuclear importing and its downstream target gene expression such as p21 and MDM2, while de-phosphorylated Hsp27 impeded this procession. Taken together, our data suggest that Hsp27, in its phosphorylated or de-phosphorylated status, plays different roles in regulating p53 pathway and cell survival.

• Authors: Yimiao Xu, Ying Diao, Shimei Qi, Xiaolong Pan, Qi Wang, Yinqiang Xin, Xiang Cao, Jie Ruan, Zhihui Zhao, Lan Luo, Chang Liu, Zhimin Yin
• Journal: Cellular signalling (Cell Signal) Vol. 25 Issue 5 Pg. 1176-85 (May 2013) ISSN: 1873-3913 [Electronic] England
• PMID: 23357534 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier Inc. All rights reserved.

Chemical References

• Antibiotics, Antineoplastic
• Cell Cycle Proteins
• Cyclin-Dependent Kinase Inhibitor p21
• DNA-Binding Proteins
• HSP27 Heat-Shock Proteins
• RNA, Small Interfering
• Tumor Suppressor Protein p53
• Tumor Suppressor Proteins
• Doxorubicin
• MDM2 protein, human
• Proto-Oncogene Proteins c-mdm2
• ATM protein, human
• Ataxia Telangiectasia Mutated Proteins
• Protein Serine-Threonine Kinases

Topics

• Antibiotics, Antineoplastic (pharmacology)
• Apoptosis (drug effects)
• Ataxia Telangiectasia Mutated Proteins
• Cell Cycle Checkpoints (drug effects)
• Cell Cycle Proteins (metabolism)
• Cell Nucleus (metabolism)
• Cyclin-Dependent Kinase Inhibitor p21 (metabolism)
• DNA-Binding Proteins (metabolism)
• Down-Regulation (drug effects)
• Doxorubicin (pharmacology)
• Drug Resistance, Neoplasm
• HEK293 Cells
• HSP27 Heat-Shock Proteins (antagonists & inhibitors, genetics, metabolism)
• Humans
• MCF-7 Cells
• Phosphorylation
• Protein Serine-Threonine Kinases (metabolism)
• Proto-Oncogene Proteins c-mdm2 (metabolism)
• RNA Interference
• RNA, Small Interfering (metabolism)
• Tumor Suppressor Protein p53 (genetics, metabolism)
• Tumor Suppressor Proteins (metabolism)