Hsp27 Regulates Akt Activation and Polymorphonuclear Leukocyte Apoptosis by Scaffolding MK2 to Akt Signal Complex

Abstract

Apoptosis or programmed cell death is a series of events in a cell that leads to its death. Human polymorphonuclear leukocytes (PMN) 3 take part in host defense mechanisms against infection and inflammatory diseases. Inappropriate termination of PMN activation or failure to remove apoptotic PMNs results in inflammation. This apoptotic process has been suggested to represent an in vivo mechanism limiting oxidant-induced tissue injury caused by PMNs at the sites of inflammation. Although PMNs are constitutively committed to apoptosis from the time they enter circulation, the rate of apoptosis is not fixed. We reported that interleukin-8, granulocytemacrophage colony-stimulating factor, LTB 4 , and bacterial lipopolysaccharide (LPS) delay constitutive PMN apoptosis through the activation of the serine/threonine kinase Akt (1, 2). We demonstrated that p38 mitogen-activated protein kinase (MAPK) activity is required for Akt phosphorylation and activation (3). Additionally, we showed that Akt exists in a signaling module with p38 MAPK, MAPK-activated protein kinase-2 (MK2), and heat shock protein 27 (Hsp27) (3).Heat shock proteins represent a group of chaperone proteins that protect the cells against a variety of stresses. Besides being involved in functioning as a chaperone, Hsp27 has also been shown to regulate stability of the cytoskeleton, cell motility (4 -7), and apoptosis (8 -13). When overexpressed in tumor cells, Hsp27 increases their tumorigenicity by overexpressing MMP-9 expression and down-regulating Src tyrosine kinase Yes expression (14 -16) and protects against apoptotic cell death triggered by various stimuli, including cytotoxic drugs and ligation of the Fas/Apo-1/CD95 death receptor (17)(18)(19). Mice overexpressing Hsp27 were protected from lethal ischemia/reperfusion injury compared with their negative littermates (20). Possible mechanisms of Hsp27 anti-apoptotic activity are proposed to result from its activity as a molecular chaperone. Hsp27 binds to and inactivates the pro-apoptotic molecules Smac, caspase 3, caspase 9, and cytochrome c (21-25). Hsp27-mediated suppression of Bid translocation to the mitochondria correlates with an inhibition of cytochrome c release (25). Hsp27 has also been shown to promote survival * This work was supported by American Heart Association-Scientist Development Grant 0335278N (to M. J. R.) and National Institutes of Health Grant 1R56AI059165-01A2 (to M. J. R.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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Hsp-27 expression at diagnosis predicts poor clinical outcome in prostate cancer independent of ETS-gene rearrangement

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The p38 MAPK stress pathway as a tumor suppressor or more?

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