Gene Set: BIOCARTA_HSP27_PATHWAY

Standard name BIOCARTA_HSP27_PATHWAY
Systematic name M2587
Brief description Stress Induction of HSP Regulation
Full description or abstract Mammalian cells can respond to a variety of stresses such as heat, cold, oxidative stress, metabolic disturbance, and environmental toxins through necrotic or apoptotic cell death, while increased expression and phosphorylation of heat shock proteins such as Hsp27 can protect cells against cellular stress. Heat shock proteins commonly exhibit molecular chaperone activity and also interact with a wide variety of proteins to exert specific effects. The small heat shock protein Hsp27 exists as monomers, dimers, and oligomers in the cell, and each form has distinct activities. Oligomers are the main form of Hsp27 with molecular chaperone activity and are disrupted by phosphorylation of Hsp27 to form dimers and monomers. S-thiolation of Hsp27 on cysteine also dissociates oligomers and may provide another route of regulating the action of Hsp27 in stress. Map kinase cascades mediate Hsp27 phosphorylation. Heat stress activates the p38 kinase cascade and induces phosphorylation of Hsp27 by the downstream Map kinases Mapkapk2 and Mapkap3. Cytokines such as TNF and IL-1 can also induce Hsp27 phoshorylation through this Map kinase cascade, protecting cells in some settings against cytotoxic responses. In stressful conditions, dissociation of oligomeric Hsp27 by phosphorylation may allow lower molecular weight forms to perform other non-chaperone functions. One action of Hsp27 induced by stress is to protect cells against apoptosis and a common component of apoptotic pathways is the mitochondrial release of cytochrome c. One way that Hsp27 reduces apoptosis is by preventing the release of cytochrome c and by binding to cytochrome c in the cytosol. Downstream, Hsp27 also blocks caspase 9 activation and the subsequent activation of caspase 3, inhibiting the rest of the proteolytic caspase cascade. Yet a further role of Hsp27 in blocking apoptosis is through blocking Fas-induced apoptosis. Fas is a receptor in the TNF receptor gene family that induces apoptosis when stimulated by its cell-bound ligand, Fas-ligand. Fas induces apoptosis through two pathways, one mediated by the protein Daxx. Phosphorylated Hsp27 dimers block apoptosis by binding with Daxx and preventing downstream activation of the kinase Ask1. The interaction of Hsp27 with actin filaments may also prevent apoptosis triggered by some agents like staurosporine that damage actin. Unphosphorylated Hsp27 monomers regulate actin filament growth by binding to the end of fibers and capping them. Finally, Hsp27 appears to prevent damage to cells by reactive oxygen species (ROS), by altering the oxidative environment of the cell through induction of glutathione expression, as well as blocking apoptosis induced by ROS. Modulation of Hsp27 expression and phosphorylation may provide a useful means to alter cellular sensitivity to stress.
Collection C2: curated gene sets
      CP: canonical pathways
            CP:BIOCARTA: BioCarta gene sets
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External links https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_hsp27Pathway.gif
Organism Homo sapiens
Contributed by BioCarta
Source platform Human_RefSeq
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Compendia expression profiles GTEx compendium
Human tissue compendium (Novartis)
Global Cancer Map (Broad Institute)
NCI-60 cell lines (National Cancer Institute)
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Version history 7.0: Changed members. Upgraded to final version of Biocarta.

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