HSP27: Mechanisms of Cellular Protection Against Neuronal Injury

Stetler, R. Anne; Gao, Yanqin; Signore, Armando P.; Cao, Guodong; Chen, J.

doi:10.2174/156652409789105561

Cited by 118 publications

(109 citation statements)

References 118 publications

(155 reference statements)

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“…As a high-molecular-mass homo-oligomer, mammalian HSP27 is known to direct the refolding of denatured proteins (31). Our data suggest that the Rit-p38-MK2 signaling axis functions as a regulator of HSP27 phosphorylation, with phosphorylation reported to result in HSP27 oligomer dissociation, release of scaffolded AKT, and a loss of chaperone activity (31).…”

Section: Discussionmentioning

confidence: 82%

“…The stress-responsive protein HSP27 (heat shock protein 27) is rapidly phosphorylated in cells responding to both extracellular stimuli and a variety of stresses (14) and has been implicated in stress-dependent AKT activation (31). HSP27 normally exists as a high-order oligomer and has been shown to contribute to the regulation of cytoskeleton dynamics (26) and protein refolding (12), and overexpression of HSP27 has a potent antiapoptotic effect against a variety of cellular stresses (3).…”

mentioning

confidence: 99%

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A Rit GTPase-p38 Mitogen-Activated Protein Kinase Survival Pathway Confers Resistance to Cellular Stress

Shi

Jin

Andres

2011

Molecular and Cellular Biology

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Cells mobilize diverse signaling cascades to protect against stress-mediated injury. Ras family GTPases play a pivotal role in cell fate determination, serving as molecular switches to control the integration of multiple signaling pathways. p38 mitogen-activated protein kinase (MAPK) signaling serves as a critical fulcrum in this process, regulating networks that stimulate cellular apoptosis but also have the capacity to promote cell survival. However, relatively little is known concerning this functional dichotomy, particularly the regulation of p38-dependent survival pathways. Here, we demonstrate that the Rit GTPase promotes cell survival by directing an unexpected p38 MAPK-dependent AKT survival pathway. Following stress exposure, Rit small hairpin RNA interference (shRNAi)-treated cells display increased apoptosis and selective disruption of p38 MAPK signaling, while expression of constitutively activated Rit promotes p38-AKT-dependent cell survival. Rit, but not Ras or Rap GTPases, can associate with, and is critical for, stress-mediated activation of the scaffolded p38-MK2-HSP27-AKT prosurvival signaling complex. Together, our studies establish Rit as a central regulator of a p38 MAPK-dependent signaling cascade that functions as a critical cellular survival mechanism in response to stress.

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Section: Discussionmentioning

confidence: 82%

mentioning

confidence: 99%

A Rit GTPase-p38 Mitogen-Activated Protein Kinase Survival Pathway Confers Resistance to Cellular Stress

Shi

Jin

Andres

2011

Molecular and Cellular Biology

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“…Thus, Hsp27 may exert a proinflammatory effect, both through inducing a proinflammatory reaction (e.g., IL-8) and reducing the production of the anti-inflammatory factors (e.g., CD40 ligand and TGF-␤ 1 ) (Liu et al, 2010). In addition, Hsp27 may also function as an indirect anti-apoptotic molecule (Concannon et al, 2003) by inhibiting the proapoptotic proteins caspase-3 (Stetler et al, 2009) and Bax (Havasi et al, 2008). Since both TGF-␤ 1 and CD40 ligand may be involved in apoptosis during inflammation (Calingasan et al, 2002;Schuster and Krieglstein, 2002), reduced TGF␤1 and CD40 ligand levels induced by Hsp27 may add to the anti-apoptotic effect of Hsp27.…”

Section: Discussionmentioning

confidence: 99%

Small Heat Shock Proteins Induce a Cerebral Inflammatory Reaction

Bruinsma

Jager²,

Carrano³

et al. 2011

J. Neurosci.

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More than 80% of Alzheimer's disease (AD) patients have some degree of cerebral amyloid angiopathy (CAA). In addition to arteries and veins, capillaries can also be affected. Capillary CAA (capCAA), rather than CAA in larger vessels, is associated with flame-like amyloidbeta (A␤) deposits that may extend beyond the vessel wall and radiate into the neuropil, a phenomenon also known as "dyshoric angiopathy." A␤ deposits in AD, parenchymal as well as (cap)CAA and dyshoric angiopathy, are associated with a local inflammatory reaction, including activation of microglial cells and astrocytes that, among others, produce cytokines and reactive oxygen species. This neuroinflammatory reaction may account for at least part of the cognitive decline. In previous studies we observed that small heat shock proteins (sHsps) are associated with A␤ deposits in AD. In this study the molecular chaperones Hsp20, HspB8 and HspB2B3 were found to colocalize with CAA and capCAA in AD brains. In addition, Hsp20, HspB8 and HspB2B3 colocalized with intercellular adhesion molecule 1 (ICAM-1) in capCAA-associated dyshoric angiopathy. Furthermore, we demonstrated that Hsp20, HspB8 and HspB2B3 induced production of interleukin 8, soluble ICAM-1 and monocyte chemoattractant protein 1 by human leptomeningeal smooth muscle cells and human brain astrocytes in vitro and that Hsp27 inhibited production of transforming growth factor beta 1 and CD40 ligand. Our results suggest a central role for sHsps in the neuroinflammatory reaction in AD and CAA and thus in contributing to cognitive decline.

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“…Among these proteins, special attention has been paid to a 27 kDa heat shock protein (HSP27) that is constitutively expressed in some populations of neurons. HSP27 plays an important role in cellular defense mechanisms[242526]. A previous study showed that, 1 week after avulsion of the spinal nerve root, small motor neurons (< 500 µm 2 ) negative for HSP27 immunoreactivity died and only large (> 500 µm 2 ) HSP27-positive motor neurons survived in the spinal cord ventral horn[3].…”

Section: Introductionmentioning

confidence: 99%

Effect of dexamethasone on intelligence and hearing in preterm infants: a meta-analysis

Ruolin¹,

Zhang²,

Tao³

et al. 2014

Neural Regen Res

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In a previous study, heat shock protein 27 was persistently upregulated in ventral motor neurons following nerve root avulsion or crush. Here, we examined whether the upregulation of heat shock protein 27 would increase the survival rate of motor neurons. Rats were divided into two groups: an avulsion-only group (avulsion of the L4 lumbar nerve root only) and a crush-avulsion group (the L4 lumbar nerve root was crushed 1 week prior to the avulsion). Immunofluorescent staining revealed that the survival rate of motor neurons was significantly greater in the crush-avulsion group than in the avulsion-only group, and this difference remained for at least 5 weeks after avulsion. The higher neuronal survival rate may be explained by the upregulation of heat shock protein 27 expression in motor neurons in the crush-avulsion group. Furthermore, preconditioning crush greatly attenuated the expression of nitric oxide synthase in the motor neurons. Our findings indicate that the neuroprotective action of preconditioning crush is mediated through the upregulation of heat shock protein 27 expression and the attenuation of neuronal nitric oxide synthase upregulation following avulsion.

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HSP27: Mechanisms of Cellular Protection Against Neuronal Injury

Cited by 118 publications

References 118 publications

A Rit GTPase-p38 Mitogen-Activated Protein Kinase Survival Pathway Confers Resistance to Cellular Stress

A Rit GTPase-p38 Mitogen-Activated Protein Kinase Survival Pathway Confers Resistance to Cellular Stress

Small Heat Shock Proteins Induce a Cerebral Inflammatory Reaction

Effect of dexamethasone on intelligence and hearing in preterm infants: a meta-analysis

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