Heat shock protein 90β inhibits apoptosis of intestinal epithelial cells induced by hypoxia through stabilizing phosphorylated Akt
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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.
Abstract
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.
참고문헌 (28)
- Taylor, C. T., "Hypoxia and gastrointestinal disease", J. Mol. Med, 85, pp.1295~1300 (2007)
- Han, X., "Regulation of intestinal barrier function by signal transducer and activator of transcription 5b", Gut, 58, pp.49~58 (2009)
- Edelblum, K. L., "Regulation of apoptosis during homeostasis and disease in the intestinal epithelium", Inflamm. Bowel. Dis, 12, pp.413~424 (2006)
- Van Leeuwen, P. A., "Clinical significance of translocation", Gut, 35, pp.28~34 (1994)
- Wang, W., "The anti-apoptotic effect of heat shock protein 90 on hypoxia- mediated cardiomyocyte damage through the PI3K", Akt pathway, 2009, pp.36, 899~903
- Friedman, G. B., "Epithelial permeability induced by neutrophil transmigration is potentiated by hypoxia: role of intracellular cAMP", J. Cell. Physiol, 176, pp.76~84 (1998)
- Ikeda, H., "Apoptosis is a major mode of cell death caused by ischaemia and ischaemia", reperfusion injury to the rat intestinal epithelium, 1998, pp.42, 530~537
- Sreedhar, A. S., "Hsp90 isoforms: functions, expression and clinical importance", FEBS Lett, 562, pp.11~15 (2004)
- Prodromou, C., "Identification and structural characterization of the ATP", ADP-binding site in the Hsp90 molecular chaperone, 1997, pp.90, 65~75
- Musch, M. W., "Induction of heat shock protein 70 protects intestinal epithelial IEC-18 cells from oxidant and thermal injury", Am. J. Physiol, 270, pp.429~436 (1996)
- Holzbeierlein, J. M., "Hsp90: a drug target?", Curr. Oncol. Rep, 12, pp.95~101 (2010)
- Fujita, N., "Involvement of Hsp90 in signaling and stability of 3-phosphoinositide- dependent kinase-1", J. Biol. Chem, 277, pp.10346~10353 (2002)
- Vivanco, I., "The phosphatidylinositol 3-Kinase AKT pathway in human cancer", Nat. Rev. Cancer, 2, pp.489~501 (2002)
- Zhang, R., "Hsp90-Akt phosphorylates ASK1 and inhibits ASK1-mediated apoptosis", Oncogene, 24, pp.3954~3963 (2005)
- Gray, P. J. Jr., "Targeting Cdc37 Inhibits Multiple Signaling Pathways and Induces Growth Arrest in Prostate Cancer Cells", Cancer Res, 67, pp.11942~11950 (2007)
- Basso, A. D., "Akt Forms an Intracellular Complex with Heat Shock Protein 90 (Hsp90) and Cdc37 and Is Destabilized by Inhibitors of Hsp90 Function", J. Biol. Chem, 277, pp.39858~39866 (2002)
- Arsham, A. M., "Phosphatidylinositol 3-kinase", Akt signaling is neither required for hypoxic stabilization of HIF-1 alpha nor sufficient for HIF-1-dependent target gene transcription, 2002, pp.277, 15162~15170
- Sakamaki, J., "Arginine methylation of BCL-2 antagonist of cell death (BAD) counteracts its phosphorylation and inactivation by Akt", Proc. Natl. Acad. Sci. U.S.A, 108, pp.6085~6090 (2011)
- Koh, P. O., "Nicotinamide attenuates the ischemic brain injury-induced decrease of Akt activation and Bad phosphorylation", Neurosci. Lett, 498, pp.105~109 (2011)
- Zhang, L., "Gene expression signatures of cAMP", protein kinase A (PKA)-promoted, mitochondrial- dependent apoptosis. Comparative analysis of wild-type and cAMP-deathless S49 lymphoma cells, 2008, pp.283, 4304~4313
- Chong, Z. Z., "Erythropoietin is a novel vascular protectant through activation of Akt1 and mitochondrial modulation of cysteine proteases", Circulation, 106, pp.2973~2979 (2002)
- Sato, S., "Modulation of Akt kinase activity by binding to Hsp90", Proc. Natl. Acad. Sci. U.S.A, 97, pp.10832~10837 (2000)
- Abreu, M. T., "Modulation of barrier function during Fas-mediated apoptosis in human intestinal epithelial cells", Gastroenterology, 119, pp.1524~1536 (2000)
- Hotchkiss, R. S., "Role of apoptotic cell death in sepsis", Scand. Infect. Dis, 35, pp.585~592 (2003)
- Galea-Lauri, J., "Increased heat shock protein 90 (hsp90) expression leads to increased apoptosis in the monoblastoid cell line U937 following induction with TNF-alpha and cycloheximide: a possible role in immunopathology", J. Immunol, 157, pp.4109~4118 (1996)
- Beere, H. M., "The stress of ding': the role of heat shock proteins in the regulation of apoptosis", J. Cell Sci, 117, pp.2641~2651 (2004)
- Giustiniani, J., "Tubulin acetylation favors Hsp90 recruitment to microtubules and stimulates the signaling function of the Hsp90 clients Akt", PKB and p53, 2009, pp.21, 529~539
- Zhang, K. R., "Long-term aerobic exercise protects the heart against ischemia", reperfusion injury via PI3 kinase-dependent and Akt-mediated mechanism, 2007, pp.12, 1579~1588