Hsp27 inhibits release of mitochondrial protein Smac in multiple myeloma cells and confers dexamethasone resistance

Chauhan, Dharminder; Li, Guilan; Hideshima, Teru; Podar, Klaus; Mitsiades, Constantine S.; Mitsiades, Nicholas; Catley, Laurence; Tai, Yu Tzu; Hayashi, Toshiaki; Shringarpure, Reshma; Burger, Renate; Munshi, Nikhil C.; Ohtake, Yasuyuki; Saxena, Satya; Anderson, Kenneth C.

doi:10.1182/blood-2003-05-1417

Cited by 151 publications

(116 citation statements)

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“…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)(22)(23)(24)(25). Hsp27-mediated suppression of Bid translocation to the mitochondria correlates with an inhibition of cytochrome c release (25).…”

mentioning

confidence: 99%

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

Kausar

Johnson

et al. 2007

Journal of Biological Chemistry

127

117

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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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mentioning

confidence: 99%

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

Kausar

Johnson

et al. 2007

Journal of Biological Chemistry

127

117

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“…Mechanistic investigations have shown that HSPB1 interferes with the apoptotic pathway in several ways including the prevention of cytochrome c and Smac/DIABLO release from the mitochondria (Chauhan et al 2003a;Paul et al 2002) and direct interaction with cytochrome c LeBlanc, 2003;Samali et al 2001) and Daxx (Charrette et al 2000) thereby inhibiting their function. There is clear evidence that HSPB1 levels correlate with chemo-resistance (Schepers et al 2005;Vargas-Roig et al 1998).…”

Section: Intracellular Hsps and Resistance To Apoptosismentioning

confidence: 99%

Heat Shock Proteins in Chronic Lymphocytic Leukaemia

Dempsey-Hibbert¹,

Hoyle²,

Williams³

2012

Chronic Lymphocytic Leukemia

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“…33) HSP27 has also been shown to prevent the mitochondrial release of Smac/DIABLO that is one of mitochondrial XIAP antagonist, and thereby to confer resistance of myeloma cells to dexamethasone. 35) By contrast to the functions of HSP70 and HSP27, which act in many different steps or apoptotic pathways, HSP90 appears to operate via a more specific inhibitory mechanism. Inhibition of binding of Akt to HSP90 leads to the dephosphorylation and inactivation of Akt, resulting in the increased sensitivity of cells to the induction of apoptosis.…”

Section: Role Of Hsp Family In the Regulation Of Apoptosismentioning

confidence: 99%

The Role of Mitochondrial Chaperone Tumor Necrosis Factor-associated Protein 1 (TRAP1) in the Regulation of Apoptosis

Masuda

2011

JOURNAL OF HEALTH SCIENCE

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An increase of mitochondrial membrane permeability is one of the key events in apoptosis, since it leads to the release of mitochondrial apoptogenic factors, such as cytochrome c, into the cytoplasm that activate downstream target of apoptotic cell death. Bcl-2 family is one of the best-characterized proteins that directly regulate mitochondrial functions. A major role of the Bcl-2 family of proteins is to alter mitochondrial membrane permeability, thus controlling the release of caspase-activating cytochrome c. Recent reports describe about involvement of interesting apoptogenic regulators other than Bcl-2 family in regulation of mitochondrial function. Tumor necrosis factor receptor-associated protein 1 (TRAP1) is a member of the heat-shock family of mitochondrial proteins, and substantially homologous to members of the 90-kDa families of heat-shock proteins (HSP90). TRAP1 seems to have specific functions differ from those of other members of the HSP90 family. Downregulation of TRAP1 expression enhances the release of cytochrome c from mitochondria. Moreover, reactive oxygen species (ROS) are involved in the regulation of the TRAP1 expression, indicating that TRAP1 is a sensor that involved in ROS mediated regulation of apoptosis. Here, we describe the mechanisms underlying the regulation of mitochondrial functions during apoptosis by TRAP1.

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Hsp27 inhibits release of mitochondrial protein Smac in multiple myeloma cells and confers dexamethasone resistance

Cited by 151 publications

References 50 publications

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

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

Heat Shock Proteins in Chronic Lymphocytic Leukaemia

The Role of Mitochondrial Chaperone Tumor Necrosis Factor-associated Protein 1 (TRAP1) in the Regulation of Apoptosis

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