Regulation of the mammalian heat shock factor 1

Naidu, Sharadha Dayalan; Dinkova‐Kostova, Albena T.

doi:10.1111/febs.13999

Cited by 136 publications

(99 citation statements)

References 175 publications

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“…Several kinases have been implicated in phosphorylation of HSF1 at serine 307, including the MAPK kinase MEK and the p38 MAPK. Notably, among the p38 MAPK family members, p38d MAPK is particularly efficient catalyst of phosphorylation, whereas p38c MAPK is the most specific [33, 34]. Nonetheless, it remains unclear how these events regulate HSF1 activity in IPF fibroblasts.…”

Section: Discussionmentioning

confidence: 99%

“…However, it is now appreciated that increased post-transcriptional modification, induced via sumoylation, acetylation and phosphorylation can also contribute to impaired HSF1 activity. In these circumstances, it has been shown that modulation of HSF1 activity through Ser303/Ser307 phosphorylation and sumoylation at K298 are induced hyperactivity, thereby resulting in decline HSF1 transcriptional activation and increased oxidant-induced cellular damage [33, 34].…”

Section: Introductionmentioning

confidence: 99%

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Impaired HSF1 transactivation drives proteostasis collapse and senescent phenotype of IPF lung fibroblast

Cuevas-Mora

Roque

Sales

et al. 2020

Preprint

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Loss of proteostasis and cellular senescence are key hallmarks of aging. Recent studies suggest that lung fibroblasts from idiopathic pulmonary fibrosis (IPF) show features of cellular senescence, decline in heat shock proteins (HSPs) expression and impaired protein homeostasis (proteostasis). However, direct cause-effect relationships are still mostly unknown. In this study, we sought to investigate whether the heat shock factor 1 (HSF1), a major transcription factor that regulates the cellular HSPs network and cytoplasmic proteostasis, contributes to cellular senescence in lung fibroblasts. We found that IPF lung fibroblasts showed an upregulation in the expression of various cellular senescence markers, including β -galactosidase activity (SA-β-gal) staining, the DNA damage marker γ H2Ax, the cell cycle inhibitor protein p21, and multiple senescence-associated secretory proteins (SASP), as well as upregulation of collagen 1a1, fibronectin and alpha-smooth muscle actin (α-SMA) gene expression compared with age-matched controls. These changes were associated with impaired proteostasis, as judged by an increase in levels of p-HSF1 ser307 and HSF1 K298 sumo , downregulation of HSPs expression, and increased cellular protein aggregation. Similarly, lung fibroblasts isolated from a mouse model of bleomycin-induced lung fibrosis and mouse lung fibroblast chronically treated with H 2 O 2 showed downregulation in HSPs and increased in cellular senescence and SASP markers. Moreover, sustained pharmacologic activation of HSF1 increased the expression of HSPs, reduced cellular senescence markers and effectively reduced the expression of pro-fibrotic genes in IPF fibroblast. Our data provide evidence that the HSF1-mediated proteostasis is important for driving lung fibroblasts toward cellular senescence and a myofibroblast phenotype. We postulate that enhancing HSF1 activity could be effective in the treatment of lung fibrosis. METHODSAnimals. C57B/6J mice (8-10 weeks old) were purchased from the Jackson Laboratory (Bar Harbor, ME) and housed in a pathogen-free animal facility at Thomas Jefferson University. Throughout the study period, mice were maintained on a standard chow diet (13.5% calories from fat, 58% from carbohydrates, and 28.5% from protein) and permitted to feed ad libitum. ). They were isolated from the uninvolved periphery of the organ of six lung cancer patients. Fresh tissues were transported immediately to the laboratory for isolating fibroblasts according to procedures described before [35].Bleomycin-induced lung injury: Bleomycin sulphate (Enzo life science, BML-AP302-0050) was dissolved in phosphate buffered saline. Lung injury was induced by instilling 0.04U of bleomycin into the posterior oropharynx of anesthetized mice every other week for five doses [36]. The mice were observed following intubation to ensure complete recovery from anesthesia. Mice were euthanized 2 weeks after the last dose by exposure to carbon dioxide, and lungs were harvested for fibroblast isolation and histological preparation...

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Impaired HSF1 transactivation drives proteostasis collapse and senescent phenotype of IPF lung fibroblast

Cuevas-Mora

Roque

Sales

et al. 2020

Preprint

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show abstract

“…HSP70 major regulator is its transcription factor HSF1, whose activation is accompanied by its phosphorylation, being the Ser326 residue critical. With these premises, we searched for HSF1 expression in CLL B cells and we found that such as HSP70, HSF1 was also overexpressed in our patients.…”

Section: Discussionmentioning

confidence: 99%

HSP70/HSF1 axis, regulated via a PI3K/AKT pathway, is a druggable target in chronic lymphocytic leukemia

Frezzato

Raggi

Martini

et al. 2019

Intl Journal of Cancer

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Considering the role played by the heat shock protein of 70 kDa (HSP70) in cancer, we characterized this protein and its major regulator, the heat shock factor 1 (HSF1), in chronic lymphocytic leukemia (CLL). We found both HSP70 and HSF1 overexpressed in CLL patients, correlated to poor prognosis and abnormally localized in the nucleus of leukemic B cells. The two proteins were strictly correlated each other and their levels decreased consensually in those patients responding to in vivo therapeutic regimens. HSP70 and HSF1 inhibition was proved to be effective in inducing a dose-dependent in vitro apoptosis of CLL B cells. Considering that HSF1 is finely regulated by kinases belonging to pathways triggered by rat sarcoma (RAS), we benefited from a previous proteomic study performed in CLL patients aiming to assess the activation/expression of key signaling proteins. We found that patients showing high levels of HSP70 also expressed high Akt-Ser473, thus activating HSF1. Inhibition of PI3K, which activates AKT, reduced the expression of HSF1 and HSP70. By contrast, HSP70-low patients displayed high activation of MEK1/2 and ERK1/2, known to negatively regulate HSF1. These data demonstrate that the HSP70 expression is regulated by the modulation of HSF1 activity through the activation of RAS-regulated pathways and suggest the HSP70/HSF1 interplay as an interesting target for antileukemic therapies. Finally, inhibition of PI3K, that activates AKT, reduced the expression of HSF1 and HSP70.

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“…In mammalian cells, HSP110, HSP90, HSP70, HSP60, HSP40, and HSP27 are expressed constitutively, but their inducible forms are products of the transcriptional 'heat stress response', which is triggered by a heat shock transcription factor 1 (HSF1) whose activation results from the denaturation of intracellular proteins after any proteotoxic exposure (see Figure 3 and [55]). In vivo, the proteotoxic effects and HSF1 activation may take place upon such pathophysiological states as hypoxia (ischemia), acidosis, inflammation, edema, and others.…”

Section: Molecular Chaperones: Localization Activities and Implicatmentioning

confidence: 99%

Molecular Chaperones in Cancer Stem Cells: Determinants of Stemness and Potential Targets for Antitumor Therapy

Kabakov

Yakimova

Matchuk

2020

Cells

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Cancer stem cells (CSCs) are a great challenge in the fight against cancer because these self-renewing tumorigenic cell fractions are thought to be responsible for metastasis dissemination and cases of tumor recurrence. In comparison with non-stem cancer cells, CSCs are known to be more resistant to chemotherapy, radiotherapy, and immunotherapy. Elucidation of mechanisms and factors that promote the emergence and existence of CSCs and their high resistance to cytotoxic treatments would help to develop effective CSC-targeting therapeutics. The present review is dedicated to the implication of molecular chaperones (protein regulators of polypeptide chain folding) in both the formation/maintenance of the CSC phenotype and cytoprotective machinery allowing CSCs to survive after drug or radiation exposure and evade immune attack. The major cellular chaperones, namely heat shock proteins (HSP90, HSP70, HSP40, HSP27), glucose-regulated proteins (GRP94, GRP78, GRP75), tumor necrosis factor receptor-associated protein 1 (TRAP1), peptidyl-prolyl isomerases, protein disulfide isomerases, calreticulin, and also a transcription heat shock factor 1 (HSF1) initiating HSP gene expression are here considered as determinants of the cancer cell stemness and potential targets for a therapeutic attack on CSCs. Various approaches and agents are discussed that may be used for inhibiting the chaperone-dependent development/manifestations of cancer cell stemness.

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Regulation of the mammalian heat shock factor 1

Cited by 136 publications

References 175 publications

Impaired HSF1 transactivation drives proteostasis collapse and senescent phenotype of IPF lung fibroblast

Impaired HSF1 transactivation drives proteostasis collapse and senescent phenotype of IPF lung fibroblast

HSP70/HSF1 axis, regulated via a PI3K/AKT pathway, is a druggable target in chronic lymphocytic leukemia

Molecular Chaperones in Cancer Stem Cells: Determinants of Stemness and Potential Targets for Antitumor Therapy

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