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Endoplasmic reticulum targeted Bcl2 confers long term cell survival through phosphorylation of heat shock protein 27
Authors:Bhavya Balan Chandrika  Sathish Kumar Maney  Swathi U Lekshmi  Santhoshkumar Thankayyan Retnabhai
Institution:1. Department of Cardiology, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin 300211, People''s Republic of China;2. Department of Cardiology, Loma Linda University Medical Center, Loma Linda, CA, USA;1. Key Laboratory of Experimental Marine Biology, Institute of Oceanology, Chinese Academy of Sciences, Qingdao 266071, China;2. University of Chinese Academy of Sciences, Beijing 100049, China;3. Dalian Polytechnic University, Dalian 116034, China;4. Dalian Ocean University, Dalian 116023, China;2. Department of Dermatology, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, Guangxi, China
Abstract: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.
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