Molecularchaperones as HSF1-specific transcriptional repressors

Shi, Yanhong; Mosser, Dick D.; Morimoto, Richard I.

doi:10.1101/gad.12.5.654

Cited by 574 publications

(468 citation statements)

References 62 publications

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“…While there is no significant difference in Hsp90 mRNA levels, Hsp90 protein levels are decreased in Hsp70-overexpressing utricles compared to wild-type utricles. While Hsp70 has been shown to bind to the transactivation domain of Hsf1 to repress its transcriptional activity (Shi et al 1998), this cannot explain the decreased Hsp90 protein levels, as we saw no difference in Hsp90 mRNA levels between Hsp70-overexpressing and wild-type utricles. These data suggest that Hsp90 regulation may undergo Hsp70-dependent posttranscriptional regulation.…”

Section: Discussioncontrasting

confidence: 59%

Hsp70 Inhibits Aminoglycoside-Induced Hair Cell Death and is Necessary for the Protective Effect of Heat Shock

Taleb

Brandon

Lee

et al. 2008

JARO

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Sensory hair cells of the inner ear are sensitive to death from aging, noise trauma, and ototoxic drugs. Ototoxic drugs include the aminoglycoside antibiotics and the antineoplastic agent cisplatin. Exposure to aminoglycosides results in hair cell death that is mediated by specific apoptotic proteins, including cJun N-terminal kinase (JNK) and caspases. Induction of heat shock proteins (Hsps) is a highly conserved stress response that can inhibit JNK-and caspasedependent apoptosis in a variety of systems. We have previously shown that heat shock results in a robust upregulation of Hsps in the hair cells of the adult mouse utricle in vitro. In addition, heat shock results in significant inhibition of both cisplatin-and aminoglycoside-induced hair cell death. In our system, Hsp70 is the most strongly induced Hsp, which is upregulated over 250-fold at the level of mRNA 2 h after heat shock. Therefore, we have begun to examine the role of Hsp70 in mediating the protective effect of heat shock. To determine whether Hsp70 is necessary for the protective effect of heat shock against aminoglycoside-induced hair cell death, we utilized utricles from Hsp70.1/3 −/− mice. While heat shock inhibited gentamicin-induced hair cell death in wild-type utricles, utricles from Hsp70.1/3 −/− mice were not protected. In addition, we have examined the role of the major heat shock transcription factor, Hsf1, in mediating the protective effect of heat shock. Utricles from Hsf1 −/− mice and wild-type littermates were exposed to heat shock followed by gentamicin. The protective effect of heat shock on aminoglycoside-induced hair cell death was only observed in wildtype mice and not in Hsf1 −/− mice. To determine whether Hsp70 is sufficient to protect hair cells, we have utilized transgenic mice that constitutively overexpress Hsp70. Utricles from Hsp70-overexpressing mice and wild-type littermates were cultured in the presence of varying neomycin concentrations for 24 h. The Hsp70-overexpressing utricles were significantly protected against neomycin-induced hair cell death at moderate to high doses of neomycin. This protective effect was achieved without a heat shock. Taken together, these data indicate that Hsp70 and Hsf1 are each necessary for the protective effect of heat shock against aminoglycoside-induced death. Furthermore, overexpression of Hsp70 alone significantly inhibits aminoglycoside-induced hair cell death.

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Section: Discussioncontrasting

confidence: 59%

Hsp70 Inhibits Aminoglycoside-Induced Hair Cell Death and is Necessary for the Protective Effect of Heat Shock

Taleb

Brandon

Lee

et al. 2008

JARO

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“…These considerations suggest that the Ssb proteins might function in a feedback loop with yeast HSF, essentially analogous to the feedback loop that has been proposed for metazoan HSF and hsp70 (Morimoto, 1993;Shi et al, 1998), but not dependent on stress per se. When the rate of protein synthesis is high and the concentration of Ssb1/2p substrates is therefore also high, the Ssb proteins would be occupied and would be unavailable to bind HSF.…”

Section: Discussionmentioning

confidence: 98%

“…Because r-proteins are synthesized in excess of what can be assembled into ribosomes (Warner et al, 1985;Maicas et al, 1988), r-proteins represent a major class of short-lived proteins, with half-lives of 1-5 min (Warner, 1989). Therefore, r-proteins represent a second major class of Ssb1/2p substrates.These considerations suggest that the Ssb proteins might function in a feedback loop with yeast HSF, essentially analogous to the feedback loop that has been proposed for metazoan HSF and hsp70 (Morimoto, 1993;Shi et al, 1998), but not dependent on stress per se. When the rate of protein synthesis is high and the concentration of Ssb1/2p substrates is therefore also high, the Ssb proteins would be occupied and would be unavailable to bind HSF.…”

mentioning

confidence: 97%

Complex Regulation of the Yeast Heat Shock Transcription Factor

Bonner

Carlson

Fackenthal

et al. 2000

MBoC

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The yeast heat shock transcription factor (HSF) is regulated by posttranslational modification. Heat and superoxide can induce the conformational change associated with the heat shock response. Interaction between HSF and the chaperone hsp70 is also thought to play a role in HSF regulation. Here, we show that the Ssb1/2p member of the hsp70 family can form a stable, ATP-sensitive complex with HSF-a surprising finding because Ssb1/2p is not induced by heat shock. Phosphorylation and the assembly of HSF into larger, ATP-sensitive complexes both occur when HSF activity decreases, whether during adaptation to a raised temperature or during growth at low glucose concentrations. These larger HSF complexes also form during recovery from heat shock. However, if HSF is assembled into ATP-sensitive complexes (during growth at a low glucose concentration), heat shock does not stimulate the dissociation of the complexes. Nor does induction of the conformational change induce their dissociation. Modulation of the in vivo concentrations of the SSA and SSB proteins by deletion or overexpression affects HSF activity in a manner that is consistent with these findings and suggests the model that the SSA and SSB proteins perform distinct roles in the regulation of HSF activity. INTRODUCTIONIt has long been known that in cells of many species, including Escherichia coli and Saccharomyces cerevisiae, cell division rates are tightly coupled with the steady-state levels and rates of synthesis of ribosomal proteins and rRNA. For example, cells in rich media, with a short generation time, display higher abundance of rRNA and higher rates of synthesis of ribosomal proteins than do cells in poor media, with a long generation time. In E. coli, some of this regulation is achieved by transcriptional attenuation and translational regulation via binding of ribosomal proteins to the RNAs of target operons (Freedman et al., 1985;Cole and Nomura, 1986). In yeast, regulation is partly transcriptional, via RAP1 and its binding site, the upstream activating sequence (UAS) rpg (Herruer et al., 1987;Moehle and Hinnebusch, 1991;Kraakman et al., 1993), although much of the regulation of ribosomal protein abundance is achieved by a competition between the assembly into ribosomes and the rapid degradation of unassembled ribosomal proteins (Warner et al., 1985;Maicas et al., 1988).Growth rate control clearly modulates the level of the translational machinery, which in turn influences the overall rate of protein synthesis. Changes in the rates of protein synthesis must, in turn, have profound implications for the protein chaperone system. Newly synthesized polypeptides typically do not adopt their mature conformation immediately but instead follow a complex folding pathway. For many proteins, the cytoplasmic chaperone system plays an integral role in helping these polypeptides adopt their mature conformations (for review, see Hendrick and Hartl, 1995). The hsp70 proteins are generally believed to bind efficiently to nascent or newly synthesized polypeptides...

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“…The HSPs shield non-native or misfolded proteins and help in recovery from proteostasis imbalance. Once the chaperone reservoir reverts to normal, the HSF1 activation is attenuated by a negative feedback mechanism upon rebinding of the chaperone complex and post-translational modifications (Abravaya et al, 1992;Baler et al, 1992;Guo et al, 2001;Shi et al, 1998). This multistep and highly regulated activation of the heat shock response culminates in restoration of proteostasis.…”

Section: Ii42 Hsf1 and Stress Responsementioning

confidence: 99%