Hsp105α Suppresses the Aggregation of Truncated Androgen Receptor with Expanded CAG Repeats and Cell Toxicity

Ishihara, Keiichi; Yamagishi, Nobuyuki; Saito, Youhei; Adachi, Hiroaki; Kobayashi, Yasushi; Sobue, Gen; Ohtsuka, Kenzo; Hatayama, Takumi

doi:10.1074/jbc.m302975200

Cited by 75 publications

(55 citation statements)

References 58 publications

(47 reference statements)

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“…Overexpression of mammalian Hsp110 in Rat-1 and HeLa cells confers increased thermoresistance (22). Recently, overexpression of Hsp110 was found to suppress cell toxicity caused by induction of the polyglutamine tract-containing truncated androgen receptor (tAR) in COS-7 cells (23). These findings are consistent with the general chaperone activity demonstrated in vitro, but to date, no endogenous cellular targets have been identified.…”

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confidence: 72%

The Yeast Hsp110 Sse1 Functionally Interacts with the Hsp70 Chaperones Ssa and Ssb

Shaner¹,

Wegele

Büchner

et al. 2005

Journal of Biological Chemistry

120

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There is growing evidence that members of the extended Hsp70 family of molecular chaperones, including the Hsp110 and Grp170 subgroups, collaborate in vivo to carry out essential cellular processes. However, relatively little is known regarding the interactions and cellular functions of Sse1, the yeast Hsp110 homolog. Through co-immunoprecipitation analysis, we found that Sse1 forms heterodimeric complexes with the abundant cytosolic Hsp70s Ssa and Ssb in vivo. Furthermore, these complexes can be efficiently reconstituted in vitro using purified proteins. Binding of Ssa or Ssb to Sse1 was mutually exclusive. The ATPase domain of Sse1 was found to be critical for interaction as inactivating point mutations severely reduced interaction with Ssa and Ssb. Sse1 stimulated Ssa1 ATPase activity synergistically with the co-chaperone Ydj1, and stimulation required complex formation. Ssa1 is required for post-translational translocation of the yeast mating pheromone ␣-factor into the endoplasmic reticulum. Like ssa mutants, we demonstrate that sse1⌬ cells accumulate prepro-␣-factor, but not the co-translationally imported protein Kar2, indicating that interaction between Sse1 and Ssa is functionally significant in vivo. These data suggest that the Hsp110 chaperone operates in concert with Hsp70 in yeast and that this collaboration is required for cellular Hsp70 functions.Cells respond to protein-denaturing stresses such as heat by rapidly inducing expression of a wide array of heat shock genes. Chief among these are the molecular chaperones, highly conserved proteins that associate with and protect unfolded proteins, preventing their aggregation and supporting refolding (1). Perhaps the most abundant and well characterized chaperones are the heat shock protein 70 (Hsp70) 2 family, found in all cell types from bacteria to eukaryotes (2, 3). Hsp70s assist in protein refolding by binding of exposed hydrophobic surfaces of a substrate to a C-terminal peptide binding domain. Cycles of substrate binding and release are brought about by transition between low and high affinity binding states regulated by nucleotide occupancy in the N-terminal ATPase domain (4).In eukaryotic cells Hsp70 class chaperones can be divided into three subfamilies: 1) DnaK-like, 2) Hsp110, and 3) Grp170 (5). The budding yeast, Saccharomyces cerevisiae, possesses 14 Hsp70 homologs with family members present in the cytoplasm, endoplasmic reticulum (ER), and mitochondria (6). The most well studied Hsp70s in yeast are the cytoplasmic Ssa proteins (stress seventy A), encoded by the differentially expressed SSA1-4 genes. Ssa1-4 (collectively referred to as "Ssa") perform largely redundant functions and the presence of at least one SSA gene is required for viability (7). Ssa chaperones are involved in cellular processes such as translation, translocation of proteins across cellular membranes, and general protein folding (8). Cells depleted of Ssa exhibit multiple cellular defects, including: (i) growth arrest in G 2 /M phase, (ii) accumulation of precursor pr...

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confidence: 72%

The Yeast Hsp110 Sse1 Functionally Interacts with the Hsp70 Chaperones Ssa and Ssb

Shaner¹,

Wegele

Büchner

et al. 2005

Journal of Biological Chemistry

120

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“…HSP105 previously was shown to associate with HSP70 and HSP40 and to suppresses the ability of HSP70/HSP40 to promote protein refolding [29,39]. Although these studies indicated that HSP105 reduces the function HSP70, in opposition to this HSP105 also was reported to be a nucleotide exchange factor for HSP70, thus promoting its activity [27,28].…”

Section: Discussionmentioning

confidence: 99%

“…HSP105 is a nucleotide exchange factor for HSP70 [27,28] and prevents aggregation of mutant androgen receptors [29] and Zn/Cu superoxide dismutase [30]. HSP105 attenuates staurosporineinduced apoptosis [31], but overexpressed HSP105α in mouse embryonal F9 cells enhanced apoptosis in response to oxidative stress [32].…”

Section: Introductionmentioning

confidence: 99%

HSP105 interacts with GRP78 and GSK3 and promotes ER stress-induced caspase-3 activation

Meares

Zmijewska

Jope

2008

Cellular Signalling

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Stress of the endoplasmic reticulum (ER stress) is caused by the accumulation of misfolded proteins, which occurs in many neurodegenerative diseases. ER stress can lead to adaptive responses or apoptosis, both of which follow activation of the unfolded protein response (UPR). Heat shock proteins (HSP) support the folding and function of many proteins, and are important components of the ER stress response, but little is known about the role of one of the major large HSPs, HSP105. We identified several new partners of HSP105, including glycogen synthase-3 (GSK3), a promoter of ER stress-induced apoptosis, and GRP78, a key component of the UPR. Knockdown of HSP105 did not alter UPR signaling after ER stress, but blocked caspase-3 activation after ER stress. In contrast, caspase-3 activation by genotoxic stress was unaffected by knockdown of HSP105, suggesting ER stress-specificity in the apoptotic action of HSP105. However, knockdown of HSP105 did not alter cell survival after ER stress, but instead diverted signaling to a caspase-3-independent cell death pathway, indicating that HSP105 is necessary for apoptotic signaling after UPR activation by ER stress. Thus, HSP105 appears to chaperone the responses to ER stress through its interactions with GRP78 and GSK3, and without HSP105 cell death following ER stress proceeds by a noncaspase-3-dependent process.

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“…The human HSP105 family has a high molecular mass and consists of HSP105α and HSP105β cytoplasmic forms (Ishihara et al, 2003;Doak et al, 2004). In previous studies, HSP105 could show to suppress apoptosis in macrophage and neuronal cell.…”

Section: Prevalence and Pathogenesis Of Barrett's Esophagus In Luoyanmentioning

confidence: 99%

Prevalence and Pathogenesis of Barrett's Esophagus in Luoyang, China

Zhang

Wang²,

Gao³

2012

Asian Pacific Journal of Cancer Prevention

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Background: Prevalence of Barrett's esophagus (BE) in Luoyang, China, has not been reported, and its pathogenesis is controversial. The aim of this study was therefore to investigate the prevalence of BE and its underlying factors in the city of Luoyang. Method: This was a prospective study in one center. Many patients were analyzed using endoscopy who showed upper gastrointestinal symptoms between August 2006 and June 2007. In addition, the effect of apoptosis-related proteins and heat shock proteins upon BE's pathogenesis were also investigated by an immunohistochemical protocol. Results: Prevalence of BE was at 4.55% and the mean age of those affected was about 10 years older than for esophagitis. Typical reflux symptoms were significantly lower than with esophagitis, whereas signs of caspase-3 and HSP105 elevation were significantly higher. Expression of TERT, HSP70 and HSP90α in BE cases was significantly lower than in esophagitis. However, there was no statistical difference between the two groups in expression of HSP27. Conclusions: The prevalence of BE is high in Luoyang, which could result from esophagitis despite typical reflux symptoms being relatively uncommon. Initiation and development of BE might be the result of accelerated proliferation, apoptosis and differentiation of original cells to intestinal epithelium.

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Hsp105α Suppresses the Aggregation of Truncated Androgen Receptor with Expanded CAG Repeats and Cell Toxicity

Cited by 75 publications

References 58 publications

The Yeast Hsp110 Sse1 Functionally Interacts with the Hsp70 Chaperones Ssa and Ssb

The Yeast Hsp110 Sse1 Functionally Interacts with the Hsp70 Chaperones Ssa and Ssb

HSP105 interacts with GRP78 and GSK3 and promotes ER stress-induced caspase-3 activation

Prevalence and Pathogenesis of Barrett's Esophagus in Luoyang, China

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