Deficient induction of human hsp70 heat shock gene transcription in Y79 retinoblastoma cells despite activation of heat shock factor 1.

Mathur, Sameer K.; Sistonen, Lea; Brown, Ian R.; Murphy, Shawn P.; Sarge, Kevin D.; Morimoto, Richard I.

doi:10.1073/pnas.91.18.8695

Cited by 66 publications

(36 citation statements)

References 42 publications

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“…Notably, a constitutively active mutant of HSF1 (⌬HSF) very efficiently induced expression of Hsp72, showing that the endogenous Hsp72 gene in ScN2a cells has a functional promoter. This is in contrast to some cell lines described earlier (20, 64 -66) in which a chromatin-mediated effect accounted for an impaired Hsp72 expression after stress (67,68). Based on the finding that in ScN2a cells HSF1 activity after stress was sufficient to induce trimer formation yet insufficient to promote transactivation competence, we directed our attention to the activation/deactivation pathway of HSF1.…”

Section: Discussioncontrasting

confidence: 47%

Geldanamycin Restores a Defective Heat Shock Responsein Vivo

Winklhofer

Reintjes

Hoener

et al. 2001

Journal of Biological Chemistry

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Induced expression of heat shock proteins (Hsps) plays a central role in promoting cellular survival after environmental and physiological stress. We have previously shown that scrapie-infected mouse neuroblastoma (ScN2a) cells fail to induce the expression of Hsp72 and Hsp28 after various stress conditions. Here we present evidence that this impaired stress response is due to an altered regulation of HSF1 activity. Upon stress in ScN2a cells, HSF1 was converted into hyperphosphorylated trimers but failed to acquire transactivation competence. A kinetic analysis of HSF1 activation revealed that in ScN2a cells trimer formation after stress was efficient, but disassembly of trimers proceeded much faster than in the uninfected cell line. Geldanamycin, a Hsp90-binding drug, significantly delayed disassembly of HSF1 trimers after a heat shock and restored stressinduced expression of Hsp72 in ScN2a cells. Heat-induced Hsp72 expression required geldanamycin to be present; following removal of the drug ScN2a cells again lost their ability to mount a stress response. Thus, our studies show that a defective stress response can be pharmacologically restored and suggest that the HSF1 deactivation pathway may play an important role in the regulation of Hsp expression.

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Section: Discussioncontrasting

confidence: 47%

Geldanamycin Restores a Defective Heat Shock Responsein Vivo

Winklhofer

Reintjes

Hoener

et al. 2001

Journal of Biological Chemistry

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“…Of particular interest are studies on the HSR in the brain and during aging (Sprang and Brown 1987;Blake et al 1991;Shamovsky and Gershon 2004) that have observed restricted expression of HS in different regions of the brain. Likewise, for neuronal cells in culture, the selective induction of HS genes has been observed; for example, in human neuroblastoma Y79 cells, HSF-1 is activated yet transcription of the Hsp90 but not Hsp70 gene is observed (Mathur et al 1994). In primary hippocampal neurons from neonatal rat embryos, only HSF-2 but not HSF-1 is expressed; consequently, hippocampal neurons are deficient for the HSR, whereas cocultured astrocytes exhibit a robust HSR (Marcuccilli et al 1996).…”

Section: Stress-inducible Regulation Of Chaperone Networkmentioning

confidence: 99%

The Heat Shock Response: Systems Biology of Proteotoxic Stress in Aging and Disease

Morimoto

2011

Cold Spring Harbor Symposia on Quantitative Biology

357

302

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“…Although the importance of HSF1 in the regulation of mammalian hsp70 expression is well-established, recent data indicate that activation of HSF1 is not sufficient for the induction of hsp70 gene expression (36,39,43). Studies from our laboratory and others suggest the existence of an additional regulatory factor or factors (18,36).…”

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confidence: 93%

Modulation of Thermal Induction of hsp70 Expression by Ku Autoantigen or Its Individual Subunits

Yang

Nussenzweig

et al. 1996

Molecular and Cellular Biology

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Previously, we proposed a dual control mechanism for the regulation of the heat shock response in mammalian cells: a positive control mediated by the heat shock transcription factor HSF1 and a negative control mediated by the constitutive heat shock element-binding factor (CHBF). To study the physiological role of CHBF in the regulation of heat shock response, we purified CHBF to apparent homogeneity and showed it to be identical to the Ku autoantigen, a heterodimer consisting of 70-kDa (Ku-70) and 86-kDa (Ku-80) polypeptides. To study further the functional significance of Ku/CHBF in the cellular response to heat shock, we established rodent cell lines that stably and constitutively overexpressed one or both subunits of the human Ku protein, and examined the thermal induction of hsp70 and other heat shock proteins in these Ku-overexpressing cells. We show that expression of the human Ku-70 and Ku-80 subunits jointly or of the Ku-70 subunit alone specifically inhibits heat-induced hsp70 expression. Conversely, expression of human Ku-80 alone does not have this effect. Thermal induction of other heat shock proteins in all of the Ku-overexpressing cell lines appears not to be significantly affected, nor is the state of phosphorylation or the DNA-binding ability of HSF1 affected. These findings support a model in which hsp70 expression is controlled by a second regulatory factor in addition to the positive activation of HSF1. The Ku protein, specifically the Ku-70 subunit, is involved in the regulation of hsp70 gene expression.Cells and organisms respond to heat shock and a number of other environmental stresses by rapidly increasing the level of transcription of heat shock genes and the translation of their messages, leading to an elevated cellular level of the heat shock proteins (hsps). Among these proteins, hsp70 has been implicated in playing a key role in the cellular response to heat shock. Many recent studies suggest that one of the functions of hsp70 is to protect cells from thermal damage (3,17,21,29,30,44,45,53) by maintaining the native state and proper folding of cellular proteins under physiological stress (5,8,19,56), and/or by facilitating the restoration of certain cellular functions (37,48,57).In recent years, extensive studies of the mammalian heat shock transcription factor HSF1 have implicated this protein as a key positive regulatory factor in the heat shock response (1, 33-35, 59, 67). Although the importance of HSF1 in the regulation of mammalian hsp70 expression is well-established, recent data indicate that activation of HSF1 is not sufficient for the induction of hsp70 gene expression (36,39,43). Studies from our laboratory and others suggest the existence of an additional regulatory factor or factors (18,36). Experiments with extracts of control and heat-shocked cells demonstrated that rodent cells may contain two different heat shock element (HSE)-binding factors: in addition to HSF1, there appears to be a constitutive HSE-binding factor (CHBF) (22,36).Analysis of these two factors in ...

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Deficient induction of human hsp70 heat shock gene transcription in Y79 retinoblastoma cells despite activation of heat shock factor 1.

Cited by 66 publications

References 42 publications

Geldanamycin Restores a Defective Heat Shock Responsein Vivo

Geldanamycin Restores a Defective Heat Shock Responsein Vivo

The Heat Shock Response: Systems Biology of Proteotoxic Stress in Aging and Disease

Modulation of Thermal Induction of hsp70 Expression by Ku Autoantigen or Its Individual Subunits

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