HSF1 phase transition mediates stress adaptation and cell fate decisions

Gaglia, Giorgio; Rashid, Rumana; Yapp, Clarence; Joshi, Gayatri; Li, Carmen G; Lindquist, Susan; Sarosiek, Kristopher A.; Whitesell, Luke; Sorger, Peter K.; Santagata, Sandro

doi:10.1038/s41556-019-0458-3

Cited by 88 publications

(76 citation statements)

References 41 publications

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“…Small, fluid condensates enlarge into indissoluble gel-like arrangements, where HSF1 is immobilized. Consequently, chaperone gene expression decreases, leading to cell death by apoptosis [176].…”

Section: Additional Cell Death Responsesmentioning

confidence: 99%

Proteotoxic Stress and Cell Death in Cancer Cells

Brancolini

Iuliano

2020

Cancers

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To maintain proteostasis, cells must integrate information and activities that supervise protein synthesis, protein folding, conformational stability, and also protein degradation. Extrinsic and intrinsic conditions can both impact normal proteostasis, causing the appearance of proteotoxic stress. Initially, proteotoxic stress elicits adaptive responses aimed at restoring proteostasis, allowing cells to survive the stress condition. However, if the proteostasis restoration fails, a permanent and sustained proteotoxic stress can be deleterious, and cell death ensues. Many cancer cells convive with high levels of proteotoxic stress, and this condition could be exploited from a therapeutic perspective. Understanding the cell death pathways engaged by proteotoxic stress is instrumental to better hijack the proliferative fate of cancer cells.

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Section: Additional Cell Death Responsesmentioning

confidence: 99%

Proteotoxic Stress and Cell Death in Cancer Cells

Brancolini

Iuliano

2020

Cancers

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“…Reduced TUNEL staining and reduced tumor-free survival was reported in Hsf1+/+ Neu+ experimental tumors compared to Hsf1+/− Neu+, indicating higher rates of apoptosis in Hsf1+/− tumors [63]. A strong relationship between HSF1 and cell survival was also demonstrated recently in a study by Gaglia et al, whereby the localization of HSF1 to nuclear stress bodies at the single-cell level was negatively correlated with both HSF1 transcriptional activity and cell survival after stress in human osteosarcoma cells [31].…”

Section: Hsf1 Promotes Evasion Of Cancer Cell Death and Senescencementioning

confidence: 51%

“…Each monomer of the HSF1 trimer binds to a 5 -nGAAn-3 unit within a heat shock element (HSE) motif found near the transcription start site of HSP genes [28]. The winged helix-turn-helix DBD is the most well-conserved and structured domain across all HSF orthologs [6,[29][30][31]. This conservation contrasts with the remainder of the HSF1 sequence, which is predominantly unstructured but interspersed with some regions of higher order [31,32], a characteristic of many key regulatory factors that interact with numerous other proteins [33].…”

Section: Introductionmentioning

confidence: 99%

“…The winged helix-turn-helix DBD is the most well-conserved and structured domain across all HSF orthologs [6,[29][30][31]. This conservation contrasts with the remainder of the HSF1 sequence, which is predominantly unstructured but interspersed with some regions of higher order [31,32], a characteristic of many key regulatory factors that interact with numerous other proteins [33]. Consequently, attempts to crystallize the full-length tertiary structure of human HSF1 have not succeeded to our knowledge, making it difficult to determine precisely the relationships between the HSF1 structure and biological function for these latter regions.…”

Section: Introductionmentioning

confidence: 99%

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HSF1: Primary Factor in Molecular Chaperone Expression and a Major Contributor to Cancer Morbidity

Prince

Lang

Guerrero-Gimenez

et al. 2020

Cells

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Heat shock factor 1 (HSF1) is the primary component for initiation of the powerful heat shock response (HSR) in eukaryotes. The HSR is an evolutionarily conserved mechanism for responding to proteotoxic stress and involves the rapid expression of heat shock protein (HSP) molecular chaperones that promote cell viability by facilitating proteostasis. HSF1 activity is amplified in many tumor contexts in a manner that resembles a chronic state of stress, characterized by high levels of HSP gene expression as well as HSF1-mediated non-HSP gene regulation. HSF1 and its gene targets are essential for tumorigenesis across several experimental tumor models, and facilitate metastatic and resistant properties within cancer cells. Recent studies have suggested the significant potential of HSF1 as a therapeutic target and have motivated research efforts to understand the mechanisms of HSF1 regulation and develop methods for pharmacological intervention. We review what is currently known regarding the contribution of HSF1 activity to cancer pathology, its regulation and expression across human cancers, and strategies to target HSF1 for cancer therapy.

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“…YAP and TAZ, pervasively activated transcription factors in cancers, promote specific gene expression through phase separation (Cai et al, 2019;Franklin & Guan, 2020;Lu et al, 2020). Moreover, heat shock transcription factor 1 (HSF1), which is closely associated with malignant evolution of cancers, forms phase-separated nuclear stress bodies that can sequester HSF1 and thus down-regulate its function (Gaglia et al, 2020). As transcription proceeds, positive transcription elongation factor b (P-TEFb) facilitates the hyperphosphorylation of the C-terminal domain (CTD) of human RNA polymerase II (RNA Pol II) by inducing phase separation (Boehning et al, 2018;Guo et al, 2019;Lu et al, 2018).…”

Section: Transcriptionmentioning

confidence: 99%

Protein phase separation: A novel therapy for cancer?

Wang

Chen

et al. 2020

British J Pharmacology

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In recent years, phase separation has been increasingly reported to play a pivotal role in a wide range of biological processes. Due to the close relationships between cancer and disorders in intracellular physiological function, the identification of new mechanisms involved in intracellular regulation has been regarded as a new direction for cancer therapy. Introducing the concept of phase separation into complex descriptions of disease mechanisms may provide many different insights. Here, we review the recent findings on the phase separation of cancer‐related proteins, describing the possible relationships between phase separation and key proteins associated with cancer and indicate possible regulatory modalities, especially drug candidates for phase separation, which may provide more effective strategies for cancer therapy.

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HSF1 phase transition mediates stress adaptation and cell fate decisions

Cited by 88 publications

References 41 publications

Proteotoxic Stress and Cell Death in Cancer Cells

Proteotoxic Stress and Cell Death in Cancer Cells

HSF1: Primary Factor in Molecular Chaperone Expression and a Major Contributor to Cancer Morbidity

Protein phase separation: A novel therapy for cancer?

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