Heat shock protein 90β inhibits apoptosis of intestinal epithelial cells induced by hypoxia through stabilizing phosphorylated Akt.
Intestinal epithelial cell (IEC) apoptosis induced by hypoxia compromise intestinal epithelium barrier function. Both Akt and Hsp90 have cytoprotective function. However, the specific role of Akt and Hsp90β in IEC apoptosis induced by hypoxia has not been explored. We confirmed that hypoxia-induced apoptosis was reduced by Hsp90β overexpression but enhanced by decreasing Hsp90β expression. Hsp90β overexpression enhanced BAD phosphorylation and thus reduced mitochondrial release of cytochrome C. Reducing Hsp90β expression had opposite effects. The protective effect of Hsp90β against apoptosis was negated by LY294002, an Akt inhibitor. Further study showed that Akt phosphorylation was enhanced by Hsp90β, which was not due to the activation of upstream PI3K and PDK1 but because of stabilization of pAkt via direct interaction between Hsp90β and pAkt. These results demonstrate that Hsp90β may play a significant role in protecting IECs from hypoxia-induced apoptosis via stabilizing pAkt to phosphorylate BAD and reduce cytochrome C release.
Institute of Burn Research, Southwest Hospital, State Key Laboratory of Trauma, Burns and Combined Injury, Third Military Medical University, Chongqing, China.
Shuai
S
Zhang
Yong
Y
Sun
Zhiqiang
Z
Yuan
Ying
Y
Li
Xiaolu
X
Li
Zhenyu
Z
Gong
Yizhi
Y
Peng
D017209:Apoptosis / Q000187:drug effects; D018938:Caco-2 Cells; D015687:Cell Hypoxia; D002867:Chromones / Q000494:pharmacology; D045304:Cytochromes c / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007422:Intestines / Q000166:cytology; D008928:Mitochondria / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism
D002867:Chromones; D018841:HSP90 Heat-Shock Proteins; C493165:HSP90AB1 protein, human; D009025:Morpholines; D034741:RNA, Small Interfering; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D045304:Cytochromes c; D051057:Proto-Oncogene Proteins c-akt