Endoplasmic reticulum targeted Bcl2 confers long term cell survival through phosphorylation of heat shock protein 27.
Overexpression of anti-apoptotic Bcl2 family proteins is often seen in cancers rendering them insensitive to apoptosis inducing anticancer strategies. Anti-apoptotic Bcl2 family proteins are associated with different organelles like mitochondria and endoplasmic reticulum (ER) and exert their anti-apoptotic activity by inhibiting the release of Cyt.C from mitochondria irrespective of its localization. Here, we have identified a long term survival function for Bcl2 targeted at ER in mammalian system compared to wild type Bcl2 that is mediated by enhanced phosphorylation of heat shock protein 27 at ser 15, 78 and 82 sites with inhibition of caspase9 activity. Phosphorylation of hsp27 was prevented and the survival of ER-Bcl2 cells was reversed by inhibiting p38 and MEK suggesting that these kinases can act as the upstream targets for hsp27 phosphorylation. The results suggest that Bcl2 possess additional survival function in the regulation of apoptosis which is primarily regulated by its association with the ER in an hsp27 dependent manner. The interplay of both hsp27 and ER-Bcl2 in providing long term survival to cancer cells is interesting since both of these proteins are overexpressed in tumors with aggressive phenotype. The results suggest that spatial localization of Bcl2 family proteins also play a key role in long term survival of cancers indicating another level of functional regulation of Bcl2 in cancer cell survival.
Chandrika
Bhavya Balan
BB
Integrated Cancer Research, Rajiv Gandhi Centre for Biotechnology, Poojappura, Thycaud PO, Thiruvananthapuram, Kerala 695014, India.
Maney
Sathish Kumar
SK
Lekshmi
Swathi U
SU
Retnabhai
Santhoshkumar Thankayyan
ST
D017209:Apoptosis / Q000502:physiology; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000502:physiology; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D045325:HCT116 Cells; D055551:HSP27 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D010766:Phosphorylation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D014162:Transfection; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D061945:Caspase Inhibitors; D055551:HSP27 Heat-Shock Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020169:Caspases