Phosphorylation-dependent Cellular Localization and Thermoprotective Role of Heat Shock Protein 25 in Hippocampal Progenitor Cells

Geum, Dongho; Son, Gi Hoon; Kim, Kyungjin

doi:10.1074/jbc.m104396200

Cited by 120 publications

(112 citation statements)

References 41 publications

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“…In human keratinocyte cultures, inhibitors of p38MAPK prevented PV IgG-induced phosphorylation of HSP27 and, more importantly, prevented the early cytoskeletal changes associated with loss of cell-cell adhesion (14). We suggested that the observed effects may be important to the mechanism of PV IgG-induced acantholysis because HSP27 has been shown to regulate both actin (17)(18)(19) and intermediate filaments (20,21). Furthermore, p38MAPK-mediated phosphorylation of HSP27 had been shown to regulate the cytoskeleton (22)(23)(24).…”

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confidence: 89%

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p38MAPK inhibition prevents disease in pemphigus vulgaris mice

Berkowitz¹,

Hu²,

Warren³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

206

197

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Pemphigus vulgaris (PV) is a life-threatening autoimmune blistering skin disease characterized by detachment of keratinocytes (acantholysis). It has been proposed that PV IgG might trigger signaling and that this process may lead to acantholysis. Indeed, we recently identified a rapid and dose-dependent phosphorylation of p38 mitogen-activated protein kinase (p38MAPK) and heat shock protein (HSP) 27 after binding of PV antibodies to cultured keratinocytes. In human keratinocyte cultures, inhibitors of p38MAPK prevented PV IgG-induced phosphorylation of HSP27 and, more importantly, prevented the early cytoskeletal changes associated with loss of cell-cell adhesion. This study was undertaken to (i) determine whether p38MAPK and HSP25, the murine HSP27 homolog, were similarly phosphorylated in an in vivo model of PV and (ii) investigate the potential therapeutic use of p38MAPK inhibition to block blister formation in an animal model of PV. We now report that p38MAPK inhibitors prevented PV blistering disease in vivo. Targeting the end-organ by inhibiting keratinocyte desmosome signaling may be effective for treating desmosome autoimmune blistering disorders.autoimmune ͉ signaling P emphigus vulgaris (PV) is a life-threatening autoimmune blistering disease where the autoimmune response targets the epidermis and mucosal epithelia, resulting in f laccid blisters and erosions. The loss of epithelial integrity disrupts the skin barrier function, putting patients at risk for infection as well as f luid and electrolyte imbalance. Before the introduction of systemic corticosteroids, the disease was highly lethal. Although the mortality has been reduced through the use of steroids and potent immunosuppressive drugs, the disease remains lethal, and patients often suffer from and may succumb to the secondary effects of the medications used to treat the disease.In PV, IgG autoantibodies that bind to the surface of epithelial cells are pathogenic. IgG purified from PV patient sera causes blistering in mouse models (1, 2). In the PV IgG passive transfer model, autoantibodies purified from patient sera bind to keratinocyte desmoglein 3 (dsg3) (3-5) and induce loss of cell-cell adhesion, reproducing the clinical and histological features of the human disease (1, 2). In both the human disease and the PV mouse model, gentle friction of perilesional skin causes sloughing of epidermal sheets (Nikolsky's sign). Although the model mimics aspects of the disease, the molecular mechanisms of blister formation remain unresolved. In the passive transfer model, the epidermal cell-cell detachment induced by PV autoantibodies is neither Fc-(6), complement-(7), nor plasminogen activator-dependent (8). Thus, the PV passive transfer mouse model represents an end-organ damage model triggered by anti-dsg3 autoantibodies.It has been proposed that PV IgG might trigger signaling and that this process may lead to acantholysis (9 -16). Indeed, we recently identified a rapid and dose-dependent phosphorylation of p38 mitogen-activated protein kinase (p38MA...

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confidence: 89%

“…HSP27 and the related murine protein HSP25 function in signal transduction where they may regulate the actin (17)(18)(19) and intermediate filament (20,21) cytoskeleton. Additionally, p38MAPK-mediated phosphorylation of HSP27 modulates its regulation of the cytoskeleton (22)(23)(24).…”

Section: Discussionmentioning

confidence: 99%

p38MAPK inhibition prevents disease in pemphigus vulgaris mice

Berkowitz¹,

Hu²,

Warren³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

206

197

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“…For Hsp27, the extent of phosphorylation is high (5,14), and phosphorylation is required for thermotolerance (19,49,50). For ␣B-crystallin, the extent of phosphorylation is low (6,13), and the role of phosphorylation in thermotolerance is not known.…”

Section: Shsps Protect Cap-dependent Translation After Heat Shockmentioning

confidence: 99%

“…For Hsp27 and ␣B-crystallin, phosphorylation has been shown to prevent complex formation in vitro (15)(16)(17), resulting in significant decrease in chaperone activity (16 -18). Phosphorylationmimicked Hsp27 protects cells from heat stress but not from oxidative stress (16,19,20).…”

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confidence: 99%

Translational Thermotolerance Provided by Small Heat Shock Proteins Is Limited to Cap-dependent Initiation and Inhibited by 2-Aminopurine

Doerwald

Onnekink

Genesen

et al. 2003

Journal of Biological Chemistry

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Heat shock results in inhibition of general protein synthesis. In thermotolerant cells, protein synthesis is still rapidly inhibited by heat stress, but protein synthesis recovers faster than in naive heat-shocked cells, a phenomenon known as translational thermotolerance. Here we investigate the effect of overexpressing a single heat shock protein on cap-dependent and cap-independent initiation of translation during recovery from a heat shock. When overexpressing ␣B-crystallin or Hsp27, cap-dependent initiation of translation was protected but no effect was seen on cap-independent initiation of translation. When Hsp70 was overexpressed however, both cap-dependent and -independent translation were protected. This finding indicates a difference in the mechanism of protection mediated by small or large heat shock proteins. Phosphorylation of ␣B-crystallin and Hsp27 is known to significantly decrease their chaperone activity; therefore, we tested phosphorylation mutants of these proteins in this system. ␣B-crystallin needs to be in its non-phosphorylated state to give protection, whereas phosphorylated Hsp27 is more potent in protection than the unphosphorylatable form. This indicates that chaperone activity is not a prerequisite for protection of translation by small heat shock proteins after heat shock. Furthermore, we show that in the presence of 2-aminopurine, an inhibitor of kinases, among which is double-stranded RNA-activated kinase, the protective effect of overexpressing ␣B-crystallin is abolished. The synthesis of the endogenous Hsps induced by the heat shock to test for thermotolerance is also blocked by 2-aminopurine. Most likely the protective effect of ␣B-crystallin requires synthesis of the endogenous heat shock proteins. Translational thermotolerance would then be a co-operative effect of different heat shock proteins.

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“…Phosphorylation appears essential for protecting against heat shock-induced loss of clonogenic activity. It is also essential for protection against the toxic action of a number of anticancer drugs (6,27,38). In contrast, the non-phosphorylated and oligomeric species of high molecular weight are better at protecting against tumor necrosis factor-␣ or oxidative stress, suggesting different modes of protection of Hsp27 against different stresses (39,40).…”

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confidence: 99%

Essential Role of the NH2-terminal WD/EPF Motif in the Phosphorylation-activated Protective Function of Mammalian Hsp27

Thériault

Lambert

Chávez-Zobel

et al. 2004

Journal of Biological Chemistry

107

111

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Hsp27 is expressed at high levels after mild heat shock and contributes to making cells extremely resistant to subsequent treatments. The activity of the protein is regulated at the transcriptional level, but also by phosphorylation, which occurs rapidly during stress and is responsible for causing the dissociation of large 700-kDa Hsp27 oligomers into dimers. We investigated the mechanism by which phosphorylation and oligomerization modulate the protective activity of Chinese hamster Hsp27. In contrast to oligomer dissociation, which only required Ser 90

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Phosphorylation-dependent Cellular Localization and Thermoprotective Role of Heat Shock Protein 25 in Hippocampal Progenitor Cells

Cited by 120 publications

References 41 publications

p38MAPK inhibition prevents disease in pemphigus vulgaris mice

p38MAPK inhibition prevents disease in pemphigus vulgaris mice

Translational Thermotolerance Provided by Small Heat Shock Proteins Is Limited to Cap-dependent Initiation and Inhibited by 2-Aminopurine

Essential Role of the NH2-terminal WD/EPF Motif in the Phosphorylation-activated Protective Function of Mammalian Hsp27

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