Roles of heat shock factor 1 and 2 in response to proteasome inhibition: consequence on p53 stability

Lecomte, Sylvain; Desmots, Fabienne; Masson, Florent Le; Goff, Pascale Le; Michel, Denis; Christians, Elisabeth; Dréan, Yves Le

doi:10.1038/onc.2010.171

Cited by 35 publications

(38 citation statements)

References 46 publications

(51 reference statements)

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“…At the transcriptional level, HSF2 has been reported to positively and/or negatively modulate the expression of specific heat shock genes (21,22). On the other hand, a role of HSF2 in the regulation of proteasome activity with a consequent increase in HSP stability has also been described (53). In the case of AIRAP, we now report that HSF2 negatively regulates AIRAP expression after bortezomib treatment, further emphasizing an important modulatory role of this transcription factor during proteotoxic stress.…”

Section: Discussionmentioning

confidence: 62%

The Proteasome Inhibitor Bortezomib Is a Potent Inducer of Zinc Finger AN1-type Domain 2a Gene Expression

Rossi

Riccio

Coccia

et al. 2014

Journal of Biological Chemistry

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Background: AIRAP is a recently identified heat shock protein whose function and regulation are still not well defined. Results: Proteasome inhibition causes abundant AIRAP expression in human primary cells. Conclusion:The anticancer drug bortezomib regulates AIRAP expression through HSF1-HSF2 interplay. Significance: This study reveals how persistent proteasomal inhibition by clinically relevant concentrations of bortezomib affects heat shock response regulation and HSF-mediated AIRAP induction.

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Section: Discussionmentioning

confidence: 62%

The Proteasome Inhibitor Bortezomib Is a Potent Inducer of Zinc Finger AN1-type Domain 2a Gene Expression

Rossi

Riccio

Coccia

et al. 2014

Journal of Biological Chemistry

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“…Other sub-units such as PSMB4, PSMC5, and PSMD4 were affected less or not at all. 81 Decreased HSF2 expression is associated with adverse outcomes in prostate cancer and several other carcinomas such as breast, serous ovarian, lung, and renal. 84 In a detailed analysis of cellular processes, HSF2 suppression was predominantly connected with dysregulation of small GTPase activity leading to altered actin cytoskeleton dynamics and promotion of EMT and metastasis.…”

Section: Rbx1mentioning

confidence: 99%

“…81,82 It often binds DNA as a heterodimer or heterotrimer with the related factor HSF1 on heat shock response sequences (Figure 4c). Cellular heat shock response is activated after growth factor stimulation and oncogene activation.…”

Section: Rbx1mentioning

confidence: 99%

Proteasome expression and activity in cancer and cancer stem cells

Voutsadakis

2017

Tumour Biol.

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Proteasome is a multi-protein organelle that participates in cellular proteostasis by destroying damaged or short-lived proteins in an organized manner guided by the ubiquitination signal. By being in a central place in the cellular protein complement homeostasis, proteasome is involved in virtually all cell processes including decisions on cell survival or death, cell cycle, and differentiation. These processes are important also in cancer, and thus, the proteasome is an important regulator of carcinogenesis. Cancers include a variety of cells which, according to the cancer stem cell theory, descend from a small percentage of cancer stem cells, alternatively termed tumor-initiating cells. These cells constitute the subsets that have the ability to propagate the whole variety of cancer and repopulate tumors after cytostatic therapies. Proteasome plays a role in cellular processes in cancer stem cells, but it has been found to have a decreased function in them compared to the rest of cancer cells. This article will discuss the transcriptional regulation of proteasome sub-unit proteins in cancer and in particular cancer stem cells and the relationship of the proteasome with the pluripotency that is the defining characteristic of stem cells. Therapeutic opportunities that present from the understanding of the proteasome role will also be discussed.

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“…Involvement of HSF2 in carcinogenesis was also suggested via a mechanism that includes p53 (Lecomte et al 2010). The functional cooperation of HSF1 and HSF2 and their co-involvement in carcinogenesis, taken together with the identification of HSF1 as an attractive anti-cancer drug target, strongly implicates HSF2 in carcinogenesis (Lecomte et al 2010;Scherz-Shouval et al 2014). Despite this strong narrative, to date, no inhibitors of HSF2 are known and no attempts to develop a screening system for HSF2 inhibitors have been reported.…”

Section: Introductionmentioning

confidence: 99%

“…Recent data implicate a more extensive role for HSF2 and demonstrate its cooperation with HSF1 in the activation of molecular chaperone genes (Ostling et al 2007;Sandqvist et al 2009). Involvement of HSF2 in carcinogenesis was also suggested via a mechanism that includes p53 (Lecomte et al 2010). The functional cooperation of HSF1 and HSF2 and their co-involvement in carcinogenesis, taken together with the identification of HSF1 as an attractive anti-cancer drug target, strongly implicates HSF2 in carcinogenesis (Lecomte et al 2010;Scherz-Shouval et al 2014).…”

Section: Introductionmentioning

confidence: 99%

High-throughput screening system for inhibitors of human Heat Shock Factor 2

Smith

Bhattacharya

Williams

et al. 2015

Cell Stress and Chaperones

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Development of novel anti-cancer drug leads that target regulators of protein homeostasis is a formidable task in modern pharmacology. Finding specific inhibitors of human Heat Shock Factor 1 (hHSF1) has proven to be a challenging task, while screening for inhibitors of human Heat Shock Factor 2 (hHSF2) has never been described. We report the development of a novel system based on an in vivo cell growth restoration assay designed to identify specific inhibitors of human HSF2 in a high-throughput format. This system utilizes a humanized yeast strain in which the master regulator of molecular chaperone genes, yeast HSF, has been replaced with hHSF2 with no detrimental effect on cell growth. This replacement preserves the general regulatory patterns of genes encoding major molecular chaperones including Hsp70 and Hsp90. The controlled overexpression of hHSF2 creates a slow-growth phenotype, which is the basis of the growth restoration assay used for high-throughput screening. The phenotype is most robust when cells are cultured at 25°C, while incubation at temperatures greater than 30°C leads to compensation of the phenotype. Overexpression of hHSF2 causes overexpression of molecular chaperones which is a likely cause of the slowed growth. Our assay is characterized by two unique advantages. First, screening takes place in physiologically relevant, in vivo conditions. Second, hits in our screen will be of medically relevant potency, as compounds that completely inhibit hHSF2 function will further inhibit cell growth and therefore will not be scored as hits. This caveat biases our screening system for compounds capable of restoring hHSF2 activity to a physiologically normal level without completely inhibiting this essential system.

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Roles of heat shock factor 1 and 2 in response to proteasome inhibition: consequence on p53 stability

Cited by 35 publications

References 46 publications

The Proteasome Inhibitor Bortezomib Is a Potent Inducer of Zinc Finger AN1-type Domain 2a Gene Expression

The Proteasome Inhibitor Bortezomib Is a Potent Inducer of Zinc Finger AN1-type Domain 2a Gene Expression

Proteasome expression and activity in cancer and cancer stem cells

High-throughput screening system for inhibitors of human Heat Shock Factor 2

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