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Richard I. Morimoto - One of the best experts on this subject based on the ideXlab platform.

  • characterizing the altered cellular proteome induced by the stress independent activation of Heat Shock Factor 1
    ACS Chemical Biology, 2014
    Co-Authors: Lisa M Ryno, Richard I. Morimoto, Joseph C Genereux, Tadasuke Naito, Evan T Powers, Matthew D Shoulders, Luke R Wiseman
    Abstract:

    The Heat Shock response is an evolutionarily conserved, stress-responsive signaling pathway that adapts cellular proteostasis in response to pathologic insult. In metazoans, the Heat Shock response primarily functions through the posttranslational activation of Heat Shock Factor 1 (HSF1), a stress-responsive transcription Factor that induces the expression of cytosolic proteostasis Factors including chaperones, cochaperones, and folding enzymes. HSF1 is a potentially attractive therapeutic target to ameliorate pathologic imbalances in cellular proteostasis associated with human disease, although the underlying impact of stress-independent HSF1 activation on cellular proteome composition remains to be defined. Here, we employ a highly controllable, ligand-regulated HSF1 that activates HSF1 to levels compatible with those that could be achieved using selective small molecule HSF1 activators. Using a combination of RNAseq and quantitative proteomics, we define the impact of stress-independent HSF1 activation...

  • stress inducible regulation of Heat Shock Factor 1 by the deacetylase sirt1
    Science, 2009
    Co-Authors: Sandy D Westerheide, Julius Anckar, Stanley M Stevens, Lea Sistonen, Richard I. Morimoto
    Abstract:

    Heat Shock Factor 1 (HSF1) is essential for protecting cells from protein-damaging stress associated with misfolded proteins and regulates the insulin-signaling pathway and aging. Here, we show that human HSF1 is inducibly acetylated at a critical residue that negatively regulates DNA binding activity. Activation of the deacetylase and longevity Factor SIRT1 prolonged HSF1 binding to the Heat Shock promoter Hsp70 by maintaining HSF1 in a deacetylated, DNA–binding competent state. Conversely, down-regulation of SIRT1 accelerated the attenuation of the Heat Shock response (HSR) and release of HSF1 from its cognate promoter elements. These results provide a mechanistic basis for the requirement of HSF1 in the regulation of life span and establish a role for SIRT1 in protein homeostasis and the HSR.

  • regulation of longevity in caenorhabditis elegans by Heat Shock Factor and molecular chaperones
    Molecular Biology of the Cell, 2003
    Co-Authors: James F Morley, Richard I. Morimoto
    Abstract:

    The correlation between longevity and stress resistance observed in long-lived mutant animals suggests that the ability to sense and respond to environmental challenges could be important for the regulation of life span. We therefore examined the role of Heat Shock Factor (HSF-1), a master transcriptional regulator of stress-inducible gene expression and protein folding homeostasis, in the regulation of longevity. Down-regulation of hsf-1 by RNA interference suppressed longevity of mutants in an insulin-like signaling (ILS) pathway that functions in the nervous system of Caenorhabditis elegans to influence aging. hsf-1 was also required for temperature-induced dauer larvae formation in an ILS mutant. Using tissue-specific expression of wild-type or dominant negative HSF-1, we demonstrated that HSF-1 acts in multiple tissues to regulate longevity. Down-regulation of individual molecular chaperones, transcriptional targets of HSF-1, also decreased longevity of long-lived mutant but not wild-type animals. However, suppression by individual chaperones was to a lesser extent, suggesting an important role for networks of chaperones. The interaction of ILS with HSF-1 could represent an important molecular strategy to couple the regulation of longevity with an ancient genetic switch that governs the ability of cells to sense and respond to stress.

  • structure function analysis of the Heat Shock Factor binding protein reveals a protein composed solely of a highly conserved and dynamic coiled coil trimerization domain
    Journal of Biological Chemistry, 2002
    Co-Authors: Li Jung Tai, Sally M Mcfall, Kai Huang, Borries Demeler, Susan G Fox, Kurt Brubaker, Ishwar Radhakrishnan, Richard I. Morimoto
    Abstract:

    Abstract Heat Shock Factor-binding protein (HSBP) 1 is a small, evolutionarily conserved protein originally identified in a yeast two-hybrid screen using the trimerization domain of Heat Shock Factor (HSF) 1 as the bait. Similar in size to HSF1 trimerization domain, human HSBP1 contains two arrays of hydrophobic heptad repeats (designated HR-N and HR-C) characteristic of coiled-coil proteins. Proteins of the HSBP family are relatively small (<100 residues), comprising solely a putative coiled-coil oligomerization domain without any other readily recognizable structural or functional motif. Our biophysical and biochemical characterization of human HSBP1 reveals a cooperatively folded protein with high α-helical content and moderate stability. NMR analyses reveal a single continuous helix encompassing both HR-N and HR-C in the highly conserved central region, whereas the less conserved carboxyl terminus is unstructured and accessible to proteases. Unlike previously characterized coiled-coils, backbone15N relaxation measurements implicate motional processes on the millisecond time scale in the coiled-coil region. Analytical ultracentrifugation and native PAGE studies indicate that HSBP1 is predominantly trimeric over a wide concentration range. NMR analyses suggest a rotationally symmetric trimer. Because the highly conserved hydrophobic heptad repeats extend over 60% of HSBP1, we propose that HSBP most likely regulates the function of other proteins through coiled-coil interactions.

  • phosphorylation of serine 230 promotes inducible transcriptional activity of Heat Shock Factor 1
    The EMBO Journal, 2001
    Co-Authors: Carina I Holmberg, Ville Hietakangas, Andrey Mikhailov, Jouni O Rantanen, Marko J Kallio, Annika Meinander, Jukka Hellman, Nick Morrice, Carol Mackintosh, Richard I. Morimoto
    Abstract:

    Heat Shock Factor 1 (HSF1) is a serine-rich constitutively phosphorylated mediator of the stress response. Upon stress, HSF1 forms DNA-binding trimers, relocalizes to nuclear granules, undergoes inducible phosphorylation and acquires the properties of a transactivator. HSF1 is phosphorylated on multiple sites, but the sites and their function have remained an enigma. Here, we have analyzed sites of endogenous phosphorylation on human HSF1 and developed a phosphopeptide antibody to identify Ser230 as a novel in vivo phosphorylation site. Ser230 is located in the regulatory domain of HSF1, and promotes the magnitude of the inducible transcriptional activity. Ser230 lies within a consensus site for calcium/calmodulin-dependent protein kinase II (CaMKII), and CaMKII overexpression enhances both the level of in vivo Ser230 phosphorylation and transactivation of HSF1. The importance of Ser230 was further established by the S230A HSF1 mutant showing markedly reduced activity relative to wild-type HSF1 when expressed in hsf1−/− cells. Our study provides the first evidence that phosphorylation is essential for the transcriptional activity of HSF1, and hence for induction of the Heat Shock response.

Susan Lindquist - One of the best experts on this subject based on the ideXlab platform.

  • abstract pr07 mechanisms of stromal reprogramming mediated by Heat Shock Factor 1
    Cancer Research, 2016
    Co-Authors: Ruth Scherzshouval, Marc L Mendillo, Luke Whitesell, Giorgio Gaglia, Irit Benaharon, Andrew H Beck, Susan Lindquist
    Abstract:

    For tumors to form, progress and metastasize, they must recruit and reprogram normal cells in their microenvironment into a pro-tumorigenic stroma. Yet little is known about the pathways leading to stromal reprogramming. We hypothesized that such reprogramming would not be mediated by classic oncogenes, since the stroma is relatively genetically stable. Instead we propose that cancer cells hijack normal cytoprotective stress responses, and subvert them to enable stromal reprogramming. We found that Heat-Shock Factor 1 (HSF1), master regulator of the Heat-Shock response, plays a crucial role in this process. Across a broad range of human cancers, HSF1 is activated in cancer-associated fibroblasts (CAFs). In early stage breast and lung cancer, high stromal HSF1 activation is strongly associated with poor patient outcome. In fibroblasts co-cultured with cancer cells, HSF1 drives a transcriptional program that supports cancer phenotypes. This program is profoundly different from the transcriptional program it drives in cancer cells or in Heat-Shocked cells. Here we characterize mechanisms leading to activation of this unique stromal program and describe the contribution of cancer cells to this process. We then explore the stromal HSF1 program in patients. We apply computational and experimental approaches to define independent cancer and stromal HSF1 signatures and highlight the prognostic value of these signatures in human breast cancer. Billions of years of evolution through changing environments led organisms to develop an arsenal of cytoprotective pathways to promote their survival under stressful conditions. Our work provides insights into the ways by which tumors co-opt these normal biological networks to support their survival in the stressful tumor microenvironment. This abstract is also presented as Poster B40. Citation Format: Ruth Scherz-Shouval, Marc L. Mendillo, Giorgio Gaglia, Irit Ben-Aharon, Andrew H. Beck, Luke Whitesell, Susan Lindquist. Mechanisms of stromal reprogramming mediated by Heat Shock Factor 1. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr PR07.

  • abstract a23 cell autonomous and nonautonomous activities of Heat Shock Factor 1 support tumor initiation progression and metastasis
    Cancer Research, 2013
    Co-Authors: Ruth Scherzshouval, Sandro Santagata, Luke Whitesell, Martina Koeva, Susan Lindquist
    Abstract:

    The Heat-Shock response is a powerful transcriptional program which acts genome-wide, not only to restore the normal protein folding through the induction of Heat Shock proteins (HSP), but to re-shape global cellular pathways controlling survival, growth and metabolism. In mammals, this response is regulated primarily by the Heat Shock Factor 1 (HSF1) transcription Factor. We have previously shown that HSF1 plays a fundamental role in tumorigenesis, by promoting the survival and malignance of tumor cells, both in tissue culture and in mouse models of cancer [1]. Recently we demonstrated that HSF1 exerts its role by activating a unique transcriptional program in the cancer cells, that is distinct from the one activated during Heat Shock [2]. In breast cancer and several other types of carcinoma, we found that high HSF1 protein levels and activation of the HSF1-dependent transcriptional program are associated with poor clinical outcome [3]. Here we show that HSF1 is activated not only in the tumor cells, but also in the stromal cells infiltrating the tumor. Examining human patient samples, we find immunohistochemical evidence for activation of HSF1 in the stroma. Using mouse xenograft models and in vitro co-culture we show that HSF1 in the stroma supports tumor cell growth. Finally, expression profiling and analysis of the DNA binding pattern of HSF1 in tumors and in cell culture indicates that stromal HSF1 supports tumorigenesis by activating a unique, stroma-specific transcriptional program. Taken together, our data suggests that HSF1 acts in the cancer cells and in the stroma to activate distinct, yet complimentary transcriptional programs that will facilitate tumor initiation, progression and metastasis. References 1. Dai, C., et al., Heat Shock Factor 1 is a powerful multifaceted modifier of carcinogenesis. Cell, 2007. 130(6): p. 1005-18. 2. Mendillo, M.L., et al., HSF1 drives a transcriptional program distinct from Heat Shock to support highly malignant human cancers. Cell, 2012. 150(3): p. 549-62. 3. Santagata, S., et al., High levels of nuclear Heat-Shock Factor 1 (HSF1) are associated with poor prognosis in breast cancer. Proc Natl Acad Sci U S A, 2011. 108(45): p. 18378-83. Citation Format: Ruth Scherz-Shouval, Sandro Santagata, Martina Koeva, Luke Whitesell, Susan Lindquist. Cell autonomous and nonautonomous activities of Heat Shock Factor 1 support tumor initiation, progression, and metastasis. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr A23.

  • high levels of nuclear Heat Shock Factor 1 hsf1 are associated with poor prognosis in breast cancer
    Proceedings of the National Academy of Sciences of the United States of America, 2011
    Co-Authors: Sandro Santagata, Nan Lin, Marc L Mendillo, Laura C Collins, Susan E Hankinson, Stuart J Schnitt, Luke Whitesell, Rulla M Tamimi, Susan Lindquist
    Abstract:

    Abstract Heat-Shock Factor 1 (HSF1) is the master transcriptional regulator of the cellular response to Heat and a wide variety of other stressors. We previously reported that HSF1 promotes the survival and proliferation of malignant cells. At this time, however, the clinical and prognostic significance of HSF1 in cancer is unknown. To address this issue breast cancer samples from 1,841 participants in the Nurses’ Health Study were scored for levels of nuclear HSF1. Associations of HSF1 status with clinical parameters and survival outcomes were investigated by Kaplan–Meier analysis and Cox proportional hazard models. The associations were further delineated by Kaplan–Meier analysis using publicly available mRNA expression data. Our results show that nuclear HSF1 levels were elevated in ∼80% of in situ and invasive breast carcinomas. In invasive carcinomas, HSF1 expression was associated with high histologic grade, larger tumor size, and nodal involvement at diagnosis (P < 0.0001). By using multivariate analysis to account for the effects of covariates, high HSF1 levels were found to be independently associated with increased mortality (hazards ratio: 1.62; 95% confidence interval: 1.21–2.17; P < 0.0013). This association was seen in the estrogen receptor (ER)-positive population (hazards ratio: 2.10; 95% confidence interval: 1.45–3.03; P < 0.0001). In public expression profiling data, high HSF1 mRNA levels were also associated with an increase in ER-positive breast cancer-specific mortality. We conclude that increased HSF1 is associated with reduced breast cancer survival. The findings indicate that HSF1 should be evaluated prospectively as an independent prognostic indicator in ER-positive breast cancer. HSF1 may ultimately be a useful therapeutic target in cancer.

  • Heat Shock Factor 1 is a powerful multifaceted modifier of carcinogenesis
    Cell, 2007
    Co-Authors: Chengkai Dai, Luke Whitesell, Susan Lindquist, Arlin B Rogers
    Abstract:

    Heat Shock Factor 1 (HSF1) is the master regulator of the Heat Shock response in eukaryotes, a very highly conserved protective mechanism. HSF1 function increases survival under a great many pathophysiological conditions. How it might be involved in malignancy remains largely unexplored. We report that eliminating HSF1 protects mice from tumors induced by mutations of the RAS oncogene or a hot spot mutation in the tumor suppressor p53. In cell culture, HSF1 supports malignant transformation by orchestrating a network of core cellular functions including proliferation, survival, protein synthesis, and glucose metabolism. The striking effects of HSF1 on oncogenic transformation are not limited to mouse systems or tumor initiation; human cancer lines of diverse origins show much greater dependence on HSF1 function to maintain proliferation and survival than their nontransformed counterparts. While it enhances organismal survival and longevity under most circumstances, HSF1 has the opposite effect in supporting the lethal phenomenon of cancer.

Luke Whitesell - One of the best experts on this subject based on the ideXlab platform.

  • abstract pr07 mechanisms of stromal reprogramming mediated by Heat Shock Factor 1
    Cancer Research, 2016
    Co-Authors: Ruth Scherzshouval, Marc L Mendillo, Luke Whitesell, Giorgio Gaglia, Irit Benaharon, Andrew H Beck, Susan Lindquist
    Abstract:

    For tumors to form, progress and metastasize, they must recruit and reprogram normal cells in their microenvironment into a pro-tumorigenic stroma. Yet little is known about the pathways leading to stromal reprogramming. We hypothesized that such reprogramming would not be mediated by classic oncogenes, since the stroma is relatively genetically stable. Instead we propose that cancer cells hijack normal cytoprotective stress responses, and subvert them to enable stromal reprogramming. We found that Heat-Shock Factor 1 (HSF1), master regulator of the Heat-Shock response, plays a crucial role in this process. Across a broad range of human cancers, HSF1 is activated in cancer-associated fibroblasts (CAFs). In early stage breast and lung cancer, high stromal HSF1 activation is strongly associated with poor patient outcome. In fibroblasts co-cultured with cancer cells, HSF1 drives a transcriptional program that supports cancer phenotypes. This program is profoundly different from the transcriptional program it drives in cancer cells or in Heat-Shocked cells. Here we characterize mechanisms leading to activation of this unique stromal program and describe the contribution of cancer cells to this process. We then explore the stromal HSF1 program in patients. We apply computational and experimental approaches to define independent cancer and stromal HSF1 signatures and highlight the prognostic value of these signatures in human breast cancer. Billions of years of evolution through changing environments led organisms to develop an arsenal of cytoprotective pathways to promote their survival under stressful conditions. Our work provides insights into the ways by which tumors co-opt these normal biological networks to support their survival in the stressful tumor microenvironment. This abstract is also presented as Poster B40. Citation Format: Ruth Scherz-Shouval, Marc L. Mendillo, Giorgio Gaglia, Irit Ben-Aharon, Andrew H. Beck, Luke Whitesell, Susan Lindquist. Mechanisms of stromal reprogramming mediated by Heat Shock Factor 1. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr PR07.

  • abstract a23 cell autonomous and nonautonomous activities of Heat Shock Factor 1 support tumor initiation progression and metastasis
    Cancer Research, 2013
    Co-Authors: Ruth Scherzshouval, Sandro Santagata, Luke Whitesell, Martina Koeva, Susan Lindquist
    Abstract:

    The Heat-Shock response is a powerful transcriptional program which acts genome-wide, not only to restore the normal protein folding through the induction of Heat Shock proteins (HSP), but to re-shape global cellular pathways controlling survival, growth and metabolism. In mammals, this response is regulated primarily by the Heat Shock Factor 1 (HSF1) transcription Factor. We have previously shown that HSF1 plays a fundamental role in tumorigenesis, by promoting the survival and malignance of tumor cells, both in tissue culture and in mouse models of cancer [1]. Recently we demonstrated that HSF1 exerts its role by activating a unique transcriptional program in the cancer cells, that is distinct from the one activated during Heat Shock [2]. In breast cancer and several other types of carcinoma, we found that high HSF1 protein levels and activation of the HSF1-dependent transcriptional program are associated with poor clinical outcome [3]. Here we show that HSF1 is activated not only in the tumor cells, but also in the stromal cells infiltrating the tumor. Examining human patient samples, we find immunohistochemical evidence for activation of HSF1 in the stroma. Using mouse xenograft models and in vitro co-culture we show that HSF1 in the stroma supports tumor cell growth. Finally, expression profiling and analysis of the DNA binding pattern of HSF1 in tumors and in cell culture indicates that stromal HSF1 supports tumorigenesis by activating a unique, stroma-specific transcriptional program. Taken together, our data suggests that HSF1 acts in the cancer cells and in the stroma to activate distinct, yet complimentary transcriptional programs that will facilitate tumor initiation, progression and metastasis. References 1. Dai, C., et al., Heat Shock Factor 1 is a powerful multifaceted modifier of carcinogenesis. Cell, 2007. 130(6): p. 1005-18. 2. Mendillo, M.L., et al., HSF1 drives a transcriptional program distinct from Heat Shock to support highly malignant human cancers. Cell, 2012. 150(3): p. 549-62. 3. Santagata, S., et al., High levels of nuclear Heat-Shock Factor 1 (HSF1) are associated with poor prognosis in breast cancer. Proc Natl Acad Sci U S A, 2011. 108(45): p. 18378-83. Citation Format: Ruth Scherz-Shouval, Sandro Santagata, Martina Koeva, Luke Whitesell, Susan Lindquist. Cell autonomous and nonautonomous activities of Heat Shock Factor 1 support tumor initiation, progression, and metastasis. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr A23.

  • high levels of nuclear Heat Shock Factor 1 hsf1 are associated with poor prognosis in breast cancer
    Proceedings of the National Academy of Sciences of the United States of America, 2011
    Co-Authors: Sandro Santagata, Nan Lin, Marc L Mendillo, Laura C Collins, Susan E Hankinson, Stuart J Schnitt, Luke Whitesell, Rulla M Tamimi, Susan Lindquist
    Abstract:

    Abstract Heat-Shock Factor 1 (HSF1) is the master transcriptional regulator of the cellular response to Heat and a wide variety of other stressors. We previously reported that HSF1 promotes the survival and proliferation of malignant cells. At this time, however, the clinical and prognostic significance of HSF1 in cancer is unknown. To address this issue breast cancer samples from 1,841 participants in the Nurses’ Health Study were scored for levels of nuclear HSF1. Associations of HSF1 status with clinical parameters and survival outcomes were investigated by Kaplan–Meier analysis and Cox proportional hazard models. The associations were further delineated by Kaplan–Meier analysis using publicly available mRNA expression data. Our results show that nuclear HSF1 levels were elevated in ∼80% of in situ and invasive breast carcinomas. In invasive carcinomas, HSF1 expression was associated with high histologic grade, larger tumor size, and nodal involvement at diagnosis (P < 0.0001). By using multivariate analysis to account for the effects of covariates, high HSF1 levels were found to be independently associated with increased mortality (hazards ratio: 1.62; 95% confidence interval: 1.21–2.17; P < 0.0013). This association was seen in the estrogen receptor (ER)-positive population (hazards ratio: 2.10; 95% confidence interval: 1.45–3.03; P < 0.0001). In public expression profiling data, high HSF1 mRNA levels were also associated with an increase in ER-positive breast cancer-specific mortality. We conclude that increased HSF1 is associated with reduced breast cancer survival. The findings indicate that HSF1 should be evaluated prospectively as an independent prognostic indicator in ER-positive breast cancer. HSF1 may ultimately be a useful therapeutic target in cancer.

  • Heat Shock Factor 1 is a powerful multifaceted modifier of carcinogenesis
    Cell, 2007
    Co-Authors: Chengkai Dai, Luke Whitesell, Susan Lindquist, Arlin B Rogers
    Abstract:

    Heat Shock Factor 1 (HSF1) is the master regulator of the Heat Shock response in eukaryotes, a very highly conserved protective mechanism. HSF1 function increases survival under a great many pathophysiological conditions. How it might be involved in malignancy remains largely unexplored. We report that eliminating HSF1 protects mice from tumors induced by mutations of the RAS oncogene or a hot spot mutation in the tumor suppressor p53. In cell culture, HSF1 supports malignant transformation by orchestrating a network of core cellular functions including proliferation, survival, protein synthesis, and glucose metabolism. The striking effects of HSF1 on oncogenic transformation are not limited to mouse systems or tumor initiation; human cancer lines of diverse origins show much greater dependence on HSF1 function to maintain proliferation and survival than their nontransformed counterparts. While it enhances organismal survival and longevity under most circumstances, HSF1 has the opposite effect in supporting the lethal phenomenon of cancer.

  • induction of a Heat Shock Factor 1 dependent stress response alters the cytotoxic activity of hsp90 binding agents
    Clinical Cancer Research, 2000
    Co-Authors: Rochelle Bagatell, Ivor J Benjamin, Gillian Painemurrieta, Charles W Taylor, Elizabeth J Pulcini, Shiro Akinaga, Luke Whitesell
    Abstract:

    In addition to its classic role in the cellular stress response, Heat Shock protein 90 (Hsp90) plays a critical but less well appreciated role in regulating signal transduction pathways that control cell growth and survival under basal, nonstress conditions. Over the past 5 years, the antitumor antibiotics geldanamycin and radicicol have become recognized as selective Hsp90-binding agents (HBA) with a novel ability to alter the activity of many of the receptors, kinases, and transcription Factors involved in these cancer-associated pathways. As a consequence of their interaction with Hsp90, however, these agents also induce a marked cellular Heat Shock response. To study the mechanism of this response and assess its relevance to the anticancer action of the HBA, we verified that the compounds could activate a reporter construct containing consensus binding sites for Heat Shock Factor 1 (HSF1), the major transcriptional regulator of the vertebrate Heat Shock response. We then used transformed fibroblasts derived from HSF1 knock-out mice to show that unlike conventional chemotherapeutics, HBA increased the synthesis and cellular levels of Heat Shock proteins in an HSF1-dependent manner. Compared with transformed fibroblasts derived from wild-type mice, HSF1 knock-out cells were significantly more sensitive to the cytotoxic effects of HBA but not to doxorubicin or cisplatin. Consistent with these in vitro data, we found that systemic administration of an HBA led to marked increases in the level of Hsp72 in both normal mouse tissues and human tumor xenografts. We conclude that HBA are useful probes for studying molecular mechanisms regulating the Heat Shock response both in cells and in whole animals. Moreover, induction of the Heat Shock response by HBA will be an important consideration in the clinical application of these drugs, both in terms of modulating their cytotoxic activity as well as monitoring their biological activity in individual patients.

Albena T Dinkovakostova - One of the best experts on this subject based on the ideXlab platform.

  • regulation of the mammalian Heat Shock Factor 1
    FEBS Journal, 2017
    Co-Authors: Sharadha Dayalan Naidu, Albena T Dinkovakostova
    Abstract:

    Living organisms are endowed with the capability to tackle various forms of cellular stress due to the presence of molecular chaperone machinery complexes that are ubiquitous throughout the cell. During conditions of proteotoxic stress, the transcription Factor Heat Shock Factor 1 (HSF1) mediates the elevation of Heat Shock proteins, which are crucial components of the chaperone complex machinery and function to ameliorate protein misfolding and aggregation and restore protein homeostasis. In addition, HSF1 orchestrates a versatile transcriptional programme that includes genes involved in repair and clearance of damaged macromolecules and maintenance of cell structure and metabolism, and provides protection against a broad range of cellular stress mediators, beyond Heat Shock. Here, we discuss the structure and function of the mammalian HSF1 and its regulation by post-translational modifications (phosphorylation, sumoylation and acetylation), proteasomal degradation, and small-molecule activators and inhibitors.

Adonis Hazoume - One of the best experts on this subject based on the ideXlab platform.

  • dual regulation of spi1 pu 1 transcription Factor by Heat Shock Factor 1 hsf1 during macrophage differentiation of monocytes
    Leukemia, 2014
    Co-Authors: Gaetan Jego, David Lanneau, A De Thonel, Kevin Berthenet, Adonis Hazoume
    Abstract:

    In addition to their cytoprotective role in stressful conditions, Heat Shock proteins (HSPs) are involved in specific differentiation pathways, for example, we have identified a role for HSP90 in macrophage differentiation of human peripheral blood monocytes that are exposed to macrophage colony-stimulating Factor (M-CSF). Here, we show that deletion of the main transcription Factor involved in Heat Shock gene regulation, Heat Shock Factor 1 (HSF1), affects M-CSF-driven differentiation of mouse bone marrow cells. HSF1 transiently accumulates in the nucleus of human monocytes undergoing macrophage differentiation, including M-CSF-treated peripheral blood monocytes and phorbol ester-treated THP1 cells. We demonstrate that HSF1 has a dual effect on SPI1/PU.1, a transcription Factor essential for macrophage differentiation and whose deregulation can lead to the development of leukemias and lymphomas. Firstly, HSF1 regulates SPI1/PU.1 gene expression through its binding to a Heat Shock element within the intron 2 of this gene. Furthermore, downregulation or inhibition of HSF1 impaired both SPI1/PU.1-targeted gene transcription and macrophage differentiation. Secondly, HSF1 induces the expression of HSP70 that interacts with SPI1/PU.1 to protect the transcription Factor from proteasomal degradation. Taken together, HSF1 appears as a fine-tuning regulator of SPI1/PU.1 expression at the transcriptional and post-translational levels during macrophage differentiation of monocytes.