title: Hsp27 protects adenocarcinoma cells from UV-induced apoptosis by Akt and p21-dependent pathways of survival.
abstract: Transcriptional activation of p53 target genes, due to DNA damage, causes either apoptosis or survival by cell cycle arrest and DNA repair. However, the regulators of the choice between cell death and survival signaling have not been completely elucidated. Here, we report that human adenocarcinoma cells (MCF-7) survive UV-induced DNA damage by heat shock protein 27 (Hsp27)-assisted Akt/p21 phosphorylation/translocation. Protein levels of the p53 target genes, such as p21, Bcl-2, p38MAPK, and Akt, showed a positive correlation to Hsp27 level during 48 hours postirradiation, whereas p53 expression increased initially but started decreasing after 12 hours. Hsp27 prevented the G(1)-S phase cell cycle arrest, observed after 8 hours of post-UV irradiation, and PARP-1 cleavage was inhibited. Conversely, silencing Hsp27 enhanced G(1)-S arrest and cell death. Moreover, use of either Hsp27 or Akt small interference RNA reduced p21 phosphorylation and enhanced its retention in nuclei even after 48 hours postirradiation, resulting in enhanced cell death. Our results showed that Hsp27 expression and its direct chaperoning interaction increases Akt stability, and p21 phosphorylation and nuclear-to-cytoplasm translocation, both essential effects for the survival of UV-induced DNA-damaged cells. We conclude that the role of Hsp27 in cancer is not only for enhanced p53 proteolysis per se, rather it is also a critical determinant in p21 phosphorylation and translocation.
authors.affiliation: Division of Cardiovascular Medicine, Davis Heartand Lung Research Institute, The Ohio State University, Columbus, Ohio, USA.
authors.forename: Ragu
authors.initials: R
authors.lastname: Kanagasabai
authors.forename: Krishnamurthy
authors.initials: K
authors.lastname: Karthikeyan
authors.forename: Kaushik
authors.initials: K
authors.lastname: Vedam
authors.forename: Wang
authors.initials: W
authors.lastname: Qien
authors.forename: Qianzheng
authors.initials: Q
authors.lastname: Zhu
authors.forename: Govindasamy
authors.initials: G
authors.lastname: Ilangovan
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology*; D017209:Apoptosis / Q000502:physiology* / Q000528:radiation effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics / Q000528:radiation effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000502:physiology* / Q000528:radiation effects; D019610:Cytoprotection / Q000502:physiology* / Q000528:radiation effects; D004249:DNA Damage / Q000528:radiation effects; D055551:HSP27 Heat-Shock Proteins / Q000502:physiology* / Q000528:radiation effects; D006360:Heat-Shock Proteins; D006801:Humans; D006868:Hydrolysis / Q000528:radiation effects; D018832:Molecular Chaperones; D010766:Phosphorylation / Q000502:physiology / Q000528:radiation effects; D055550:Protein Stability / Q000528:radiation effects; D021381:Protein Transport / Q000235:genetics / Q000528:radiation effects; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology* / Q000528:radiation effects; D015398:Signal Transduction / Q000235:genetics / Q000528:radiation effects; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism / Q000528:radiation effects; D014466:Ultraviolet Rays / Q000009:adverse effects
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D055551:HSP27 Heat-Shock Proteins; C057725:HSPB1 protein, human; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D016159:Tumor Suppressor Protein p53; D051057:Proto-Oncogene Proteins c-akt