HSP90: The Rosetta stone for cellular protein dynamics?

DeZwaan, Diane C.; Freeman, Brian C.

doi:10.4161/cc.7.8.5723

Cited by 67 publications

(60 citation statements)

References 67 publications

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“…34 In support of this hypothesis, we observed that activation of PIDD is associated with Hsp90 release and that nuclear PIDD enriched in signallingcompentent PIDDosomes does no longer interact with Hsp90. In addition to the release of Hsp90 upon PIDD activation, we provide evidence that the Hsp90/PIDD interaction before activation is required for the function of PIDD in NF-kB and caspase-2 activation.…”

Section: Discussionsupporting

confidence: 72%

Regulation of PIDD auto-proteolysis and activity by the molecular chaperone Hsp90

et al. 2010

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In response to DNA damage, p53-induced protein with a death domain (PIDD) forms a complex called the PIDDosome, which either consists of PIDD, RIP-associated protein with a death domain and caspase-2, forming a platform for the activation of caspase-2, or contains PIDD, RIP1 and NEMO, important for NF-jB activation. PIDDosome activation is dependent on autoprocessing of PIDD at two different sites, generating the fragments PIDD-C and PIDD-CC. Despite constitutive cleavage, endogenous PIDD remains inactive. In this study, we screened for novel PIDD regulators and identified heat shock protein 90 (Hsp90) as a major effector in both PIDD protein maturation and activation. Hsp90, together with p23, binds PIDD and inhibition of Hsp90 activity with geldanamycin efficiently disrupts this association and impairs PIDD auto-processing. Consequently, both PIDD-mediated NF-jB and caspase-2 activation are abrogated. Interestingly, PIDDosome formation itself is associated with Hsp90 release. Characterisation of cytoplasmic and nuclear pools of PIDD showed that active PIDD accumulates in the nucleus and that only cytoplasmic PIDD is bound to Hsp90. Finally, heat shock induces Hsp90 release from PIDD and PIDD nuclear translocation. Thus, Hsp90 has a major role in controlling PIDD functional activity.

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Section: Discussionsupporting

confidence: 72%

Regulation of PIDD auto-proteolysis and activity by the molecular chaperone Hsp90

et al. 2010

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“…The hormetic effect induced by Hsp90 inhibitors may be of advantage in this regard because it potentially affects many of the pathways mediated by Hsp90, its cochaperones and the ever growing list of client proteins (Camphausen and Tofilon 2007, Dezwaan and Freeman 2008, Jarosz and Lindquist 2010.…”

Section: Discussionmentioning

confidence: 99%

Low dose Hsp90 inhibitor 17AAG protects neural progenitor cells from ischemia induced death

Bradley

Zhao

Wang

et al. 2014

J. Cell Commun. Signal.

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Stress adaptation effect provides cell protection against ischemia induced apoptosis. Whether this mechanism prevents other types of cell death in stroke is not well studied. This is an important question for regenerative medicine to treat stroke since other types of cell death such as necrosis are also prominent in the stroke brain apart from apoptosis. We report here that treatment with 17-N-Allylamino-17-demethoxygeldanamycin (17AAG), an Hsp90 inhibitor, protected neural progenitor cells (NPCs) against oxygen glucose deprivation (OGD) induced cell death in a dose dependent fashion. Cell death assays indicated that 17AAG not only ameliorated apoptosis, but also necrosis mediated by OGD. This NPC protection was confirmed by exposing cells to oxidative stress, a major stress signal prevalent in the stroke brain. Mechanistic studies demonstrated that 17AAG activated PI3K/Akt and MAPK cell protective pathways. More interestingly, these two pathways were activated in vivo by 17AAG and 17AAG treatment reduced infarct volume in a middle cerebral artery occlusion (MCAO) stroke model. These data suggest that 17AAG protects cells against major cell death pathways and thus might be used as a pharmacological conditioning agent for regenerative medicine for stroke.

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“…More recently, the core molecular chaperone machinery, including Hsp70 and Hsp90, has been suggested to take primary responsibility for maintaining a dynamic cellular environment (23,41) by taking part in transient low affinity protein-protein interactions (25). In addition some members of this group, most notably Hsp90, have more selective roles binding preferentially to specific classes of already folded proteins (42).…”

Section: Hsp90 Regulation Of Irf-1 Is Mediated By Hsp70mentioning

confidence: 99%

Cooperative Regulation of the Interferon Regulatory Factor-1 Tumor Suppressor Protein by Core Components of the Molecular Chaperone Machinery

Narayan

Eckert

Żylicz

et al. 2009

Journal of Biological Chemistry

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Our understanding of the post-translational processes involved in regulating the interferon regulatory factor-1 (IRF-1) tumor suppressor protein is limited. The introduction of mutations within the C-terminal Mf1 domain (amino acids 301-325) impacts on IRF-1-mediated gene repression and growth suppression as well as the rate of IRF-1 degradation. However, nothing is known about the proteins that interact with this region to modulate IRF-1 function. A biochemical screen for Mf1-interacting proteins has identified an LXXLL motif that is required for binding of Hsp70 family members and cooperation with Hsp90 to regulate IRF-1 turnover and activity. These conclusions are supported by the finding that Hsp90 inhibitors suppress IRF-1-dependent transcription shortly after treatment, although at later time points inhibition of Hsp90 leads to an Hsp70-dependent depletion of nuclear IRF-1. Conversely, the half-life of IRF-1 is increased by Hsp90 in an ATPase-dependent manner leading to the accumulation of nuclear but not cytoplasmic IRF-1. This study begins to elucidate the role of the Mf1 domain of IRF-1 in orchestrating the recruitment of regulatory factors that can impact on both its turnover and transcriptional activity.Interferon regulatory factor-1 (IRF-1), 3 the founding member of the interferon regulatory factor family, is a transcription factor that regulates a diverse range of target genes during the response to stimuli such as pathogen infection (1), DNA damage (2, 3), and hypoxia (4). In addition, the loss of IRF-1 can cooperate with c-Ha-ras (5) in cellular transformation; it becomes up-regulated in cells that bear oncogenic lesions (6), and deletions of IRF-1 are associated with the development of gastric and esophageal tumors, as well as some leukemias (7-9). On the basis of these observations IRF-1 has been characterized as a tumor suppressor protein. Although initially identified as a component of the IFN␤-enhanceosome complex, IRF-1 has since been demonstrated to regulate the expression of a large cohort of interferon-responsive genes involved in negative growth control (10 -12).Structurally, IRF-1 includes several domains; prominent among these is a highly conserved N-terminal sequence-specific DNA-binding domain, a transactivation domain, and a C-terminal regulatory domain known as the enhancer (13). The enhancer was originally identified as a region required for maximal IRF-1-mediated transactivation, although it does not have intrinsic transactivation potential (13). More recent structurefunction analysis has shown that the enhancer is involved in the recruitment of coactivators to IRF-1 target promoters (14) and that it can facilitate IRF-1-mediated growth suppression (15), as well as being an important determinant of the rate at which IRF-1 is degraded (15-17). Housed within the enhancer is a multifunctional subdomain that we have named Mf1 (Multifunctional 1; amino acids 301-325). This domain impacts on IRF-1-mediated transrepression of the CDK2 gene (14) and is required for maximal IRF-1-mediated...

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HSP90: The Rosetta stone for cellular protein dynamics?

Cited by 67 publications

References 67 publications

Regulation of PIDD auto-proteolysis and activity by the molecular chaperone Hsp90

Regulation of PIDD auto-proteolysis and activity by the molecular chaperone Hsp90

Low dose Hsp90 inhibitor 17AAG protects neural progenitor cells from ischemia induced death

Cooperative Regulation of the Interferon Regulatory Factor-1 Tumor Suppressor Protein by Core Components of the Molecular Chaperone Machinery

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