The possible role of heat shock factor-1 in the negative regulation of heme oxygenase-1

Poly(ADP-ribose) polymerase-1 (PARP-1)-dependent poly(ADP-ribose) formation is emerging as a key regulator of transcriptional regulation, even though the targets and underlying molecular mechanisms have not yet been clearly identified. In this study, we gathered information on the role of PARP-1 activity in the heat shock response of mouse fibroblasts. We show that DNA binding of heat shock factor (HSF)-1 was impaired by PARP-1 activity in cellular extracts, and was higher in PARP-1−/− than in PARP-1+/+ cells. No evidence for HSF-1 poly(ADP-ribosyl)ation or PARP-1 interaction was found, but a poly(ADP-ribose) binding motif was identified in the transcription factor amino acid sequence. Consistent with data on HSF-1, the expression of heat-shock protein (HSP)-70 and HSP–27 was facilitated in cells lacking PARP-1. Thermosensitivity, however, was higher in PARP-1−/− than in PARP-1+/+ cells. Accordingly, we report that heat-shocked PARP-1 null fibroblasts showed an increased activation of proapoptotic JNK and decreased transcriptional efficiency of prosurvival NF-κB compared with wild-type counterparts. The data indicate that poly(ADP-ribosyl)ation finely regulates HSF-1 activity, and emphasize the complex role of PARP-1 in the heat-shock response of mammalian cells.

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Role of heat shock factor-1 activation in the doxorubicin-induced heart failure in mice

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.01047.2009 ◽

2010 ◽

Vol 298 (6) ◽

pp. H1832-H1841 ◽

Cited By ~ 39

Author(s):

Kaushik Vedam ◽

Yoshinori Nishijima ◽

Lawrence J. Druhan ◽

Mahmood Khan ◽

Nicanor I. Moldovan ◽

...

Keyword(s):

Oxidative Stress ◽

Heart Failure ◽

Heat Shock ◽

Mrna Level ◽

Heat Shock Factor ◽

Heat Shock Factor 1 ◽

Knock Out ◽

Apoptotic Protein ◽

Shock Proteins

Treating cancer patients with chemotherapeutics, such as doxorubicin (Dox), cause dilated cardiomyopathy and congestive heart failure because of oxidative stress. On the other hand, heat shock factor-1 (HSF-1), a transcription factor for heat shock proteins (Hsps), is also known to be activated in response to oxidative stress. However, the possible role of HSF-1 activation and the resultant Hsp25 in chemotherapeutic-induced heart failure has not been investigated. Using HSF-1 wild-type (HSF-1+/+) and knock-out (HSF-1−/−) mice, we tested the hypothesis that activation of HSF-1 plays a role in the development of Dox-induced heart failure. Higher levels of Hsp25 and its phosphorylated forms were found in the failing hearts of Dox-treated HSF-1+/+ mice. More than twofold increase in Hsp25 mRNA level was found in Dox-treated hearts. Proteomic analysis showed that there is accumulation and aggregation of Hsp25 in Dox-treated failing hearts. Additionally, Hsp25 was found to coimmunoprecipitate with p53 and vice versa. Further studies indicated that the Dox-induced higher levels of Hsp25 transactivated p53 leading to higher levels of the pro-apoptotic protein Bax, but other p53-related proteins remained unaltered. Moreover, HSF-1−/− mice showed significantly reduced Dox-induced heart failure and higher survival rate, and there was no change in Bax upon treating with Dox in HSF-1−/− mice. From these results we propose a novel mechanism for Dox-induced heart failure: increased expression of Hsp25 because of oxidant-induced activation of HSF-1 transactivates p53 to increase Bax levels, which leads to heart failure.

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Abstract 1830: Role of heat shock factor 1 (HSF1) on metabolic reprogramming of T -cells

10.1158/1538-7445.am2019-1830 ◽

2019 ◽

Author(s):

Bhaumik D. Pandya ◽

Nahid M. Mivechi ◽

Dimitrios Moskophidis

Keyword(s):

T Cells ◽

Heat Shock ◽

Heat Shock Factor ◽

Metabolic Reprogramming ◽

Heat Shock Factor 1

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Induction of heme oxygenase-1 and heat shock protein 70 in rat hepatocytes: The role of calcium signaling

Cellular & Molecular Biology Letters ◽

10.2478/s11658-006-0052-0 ◽

2007 ◽

Vol 12 (1) ◽

Cited By ~ 6

Author(s):

Malte Silomon ◽

Inge Bauer ◽

Michael Bauer ◽

Julia Nolting ◽

Markus Paxian ◽

...

Keyword(s):

Gene Expression ◽

Stress Response ◽

Heat Shock ◽

Heme Oxygenase ◽

Rat Hepatocytes ◽

Glutathione Depletion ◽

Heme Oxygenase 1 ◽

Hsp70 Gene ◽

Stress Response Genes

AbstractStress response genes including heat shock proteins are induced under a variety of conditions to confer cellular protection. This study investigated the role of calcium signaling in the induction of two stress response genes, heme oxygenase-1/hsp32 and hsp70, in isolated rat hepatocytes. Both genes were induced by cellular glutathione depletion. This induction could be inhibited by BAPTA-AM. Culturing in a calcium-free medium prevented the induction of hsp70 gene expression after glutathione depletion without affecting heme oxygenase-1 gene expression. Thapsigargin increased the gene expression of heme oxygenase-1 but not that of hsp70. Thapsigargin-induced heme oxygenase-1 induction was completely inhibited by BAPTA-AM. Incubation with the Ca2+-ionophore A23187 augmented heme oxygenase-1 (two-fold) and hsp70 (5.2-fold) mRNA levels. Our data suggests a significant role of Ca2+-dependent pathways in the induction of the two stress genes. An increase in the cytoplasmic Ca2+ activity seems to play a key role in the cascade of signaling leading to the induction of the two genes. However, the source of Ca2+ that fluxes into the cytoplasm seems to be different. Our data provides evidence for a compartmentalization of calcium fluxes, i.e. the Ca2+ flux from intracellular stores (e.g. the endoplasmic reticulum) plays a major role in the induction of heme oxygenase-1. By contrast, Ca2+ flux from the extracellular medium seems to be a mechanism initiating the cellular signaling cascade leading to hsp70 gene induction.

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