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Lea Sistonen - One of the best experts on this subject based on the ideXlab platform.
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expression of HSF2 decreases in mitosis to enable stress inducible transcription and cell survival
Journal of Cell Biology, 2014Co-Authors: Alexandra N. Elsing, Marko J Kallio, Johanna K. Björk, Pia Roosmattjus, Camilla Aspelin, Heidi A Bergman, Samu V Himanen, Lea SistonenAbstract:Unless mitigated, external and physiological stresses are detrimental for cells, especially in mitosis, resulting in chromosomal missegregation, aneuploidy, or apoptosis. Heat shock proteins (Hsps) maintain protein homeostasis and promote cell survival. Hsps are transcriptionally regulated by heat shock factors (HSFs). Of these, HSF1 is the master regulator and HSF2 modulates Hsp expression by interacting with HSF1. Due to global inhibition of transcription in mitosis, including HSF1-mediated expression of Hsps, mitotic cells are highly vulnerable to stress. Here, we show that cells can counteract transcriptional silencing and protect themselves against proteotoxicity in mitosis. We found that the condensed chromatin of HSF2-deficient cells is accessible for HSF1 and RNA polymerase II, allowing stress-inducible Hsp expression. Consequently, HSF2-deficient cells exposed to acute stress display diminished mitotic errors and have a survival advantage. We also show that HSF2 expression declines during mitosis in several but not all human cell lines, which corresponds to the Hsp70 induction and protection against stress-induced mitotic abnormalities and apoptosis.
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Transcriptional response to stress in the dynamic chromatin environment of cycling and mitotic cells.
Proceedings of the National Academy of Sciences of the United States of America, 2013Co-Authors: Anniina Vihervaara, Christian Sergelius, Jenni Vasara, Malin A. H. Blom, Alexandra N. Elsing, Pia Roos-mattjus, Lea SistonenAbstract:Heat shock factors (HSFs) are the master regulators of transcription under protein-damaging conditions, acting in an environment where the overall transcription is silenced. We determined the genomewide transcriptional program that is rapidly provoked by HSF1 and HSF2 under acute stress in human cells. Our results revealed the molecular mechanisms that maintain cellular homeostasis, including HSF1-driven induction of polyubiquitin genes, as well as HSF1- and HSF2-mediated expression patterns of cochaperones, transcriptional regulators, and signaling molecules. We characterized the genomewide transcriptional response to stress also in mitotic cells where the chromatin is tightly compacted. We found a radically limited binding and transactivating capacity of HSF1, leaving mitotic cells highly susceptible to proteotoxicity. In contrast, HSF2 occupied hundreds of loci in the mitotic cells and localized to the condensed chromatin also in meiosis. These results highlight the importance of the cell cycle phase in transcriptional responses and identify the specific mechanisms for HSF1 and HSF2 in transcriptional orchestration. Moreover, we propose that HSF2 is an epigenetic regulator directing transcription throughout cell cycle progression.
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miR-18, a member of Oncomir-1, targets heat shock transcription factor 2 in spermatogenesis
Development, 2010Co-Authors: Johanna K. Björk, Anton Sandqvist, Alexandra N. Elsing, Noora Kotaja, Lea SistonenAbstract:miR-18 belongs to the Oncomir-1 or miR-17~92 cluster that is intimately associated with the occurrence and progression of different types of cancer. However, the physiological roles of the Oncomir-1 cluster and its individual miRNAs are largely unknown. Here, we describe a novel function for miR-18 in mouse. We show that miR-18 directly targets heat shock factor 2 (HSF2), a transcription factor that influences a wide range of developmental processes including embryogenesis and gametogenesis. Furthermore, we show that miR-18 is highly abundant in testis, displaying distinct cell-type-specific expression during the epithelial cycle that constitutes spermatogenesis. Expression of HSF2 and of miR-18 exhibit an inverse correlation during spermatogenesis, indicating that, in germ cells, HSF2 is downregulated by miR-18. To investigate the in vivo function of miR-18 we developed a novel method, T-GIST, and demonstrate that inhibition of miR-18 in intact seminiferous tubules leads to increased HSF2 protein levels and altered expression of HSF2 target genes. Our results reveal that miR-18 regulates HSF2 activity in spermatogenesis and link miR-18 to HSF2-mediated physiological processes such as male germ cell maturation.
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Heat shock factors: integrators of cell stress, development and lifespan
Nature Reviews Molecular Cell Biology, 2010Co-Authors: Malin Åkerfelt, Richard I. Morimoto, Lea SistonenAbstract:Heat shock factors (HSFs) are essential for all organisms to survive exposures to acute stress. They are best known as inducible transcriptional regulators of genes encoding molecular chaperones and other stress proteins. Four members of the HSF family are also important for normal development and lifespan-enhancing pathways, and the repertoire of HSF targets has thus expanded well beyond the heat shock genes. These unexpected observations have uncovered complex layers of post-translational regulation of HSFs that integrate the metabolic state of the cell with stress biology, and in doing so control fundamental aspects of the health of the proteome and ageing. Heat shock factors (HSFs) are essential for all organisms to survive exposures to stress, as they bind heat shock elements to induce transcription of heat shock proteins (HSPs). In addition, the HSFs are important regulators involved in development, lifespan and disease, thereby integrating pathways of stress responses and normal physiology. The mammalian HSF family consists of four members: HSF1, HSF2, HSF3 and HSF4. Distinct HSFs possess unique and overlapping functions, with a great variation in expression patterns, post-translational modifications (PTMs) and interacting protein partners. HSFs are composed of functional domains, of which the DNA-binding domain is best preserved. The HSF1 activation–attenuation cycle involves trimerization, strict regulation by multiple PTMs, such as acetylation, phosphorylation and sumoylation, and feedback from HSPs. Functional crosstalk between HSF family members facilitates the fine-tuning of HSF-mediated gene regulation. HSF-knockout mouse models have made it possible to identify many targets, which have further extended the impact of HSFs in developmental processes, such as oogenesis, corticogenesis and spermatogenesis. The ability to sense and respond to environmental challenges is important for lifespan, and HSF1 is a longevity factor that prevents global instability of the proteome during ageing. The life-promoting function of HSF1 is strictly controlled by the insulin and insulin-like signalling pathway in Caenorhabditis elegans . HSF1 is a potent modifier of tumorigenesis and HSF1 deficiency in mice counteracts tumour initiation and progression. HSF1 is therefore a potential cancer drug target. As many human, age-related pathologies are associated with stress and misfolded proteins, several small-molecule activators and inhibitors of HSFs could be used for pharmacologic modulation of HSF-mediated gene regulation. Heat shock factors (HSFs) are essential for survival in a stressful environment. HSFs mediate the heat shock response by binding heat shock elements present in heat shock protein (HSP) genes, thereby mediating their transcription. They are also important regulators of development, lifespan and disease.
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Heterotrimerization of Heat-Shock Factors 1 and 2 Provides a Transcriptional Switch in Response to Distinct Stimuli
Molecular Biology of the Cell, 2009Co-Authors: Anton Sandqvist, Malin Åkerfelt, Caroline Jolly, Johanna K. Björk, Zhanna Chitikova, Alexei Grichine, Claire Vourc'h, Tiina A. Salminen, Yvonne Nymalm, Lea SistonenAbstract:Organisms respond to circumstances threatening the cellular protein homeostasis by activation of heat-shock transcription factors (HSFs), which play important roles in stress resistance, development, and longevity. Of the four HSFs in vertebrates (HSF1-4), HSF1 is activated by stress, whereas HSF2 lacks intrinsic stress responsiveness. The mechanism by which HSF2 is recruited to stress-inducible promoters and how HSF2 is activated is not known. However, changes in the HSF2 expression occur, coinciding with the functions of HSF2 in development. Here, we demonstrate that HSF1 and HSF2 form heterotrimers when bound to satellite III DNA in nuclear stress bodies, subnuclear structures in which HSF1 induces transcription. By depleting HSF2, we show that HSF1-HSF2 heterotrimerization is a mechanism regulating transcription. Upon stress, HSF2 DNA binding is HSF1 dependent. Intriguingly, when the elevated expression of HSF2 during development is mimicked, HSF2 binds to DNA and becomes transcriptionally competent. HSF2 activation leads to activation of also HSF1, revealing a functional interdependency that is mediated through the conserved trimerization domains of these factors. We propose that heterotrimerization of HSF1 and HSF2 integrates transcriptional activation in response to distinct stress and developmental stimuli.
Kevin D. Sarge - One of the best experts on this subject based on the ideXlab platform.
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modulates their expression
2020Co-Authors: Donald C Wilkerson, Hollie S Skaggs, Kevin D. SargeAbstract:Although the vast majority of genomic DNA is tightly compacted during mitosis, the promoter regions of a number of genes remain in a less compacted state throughout this stage of the cell cycle. The decreased compaction of these promoter regions, which is referred to as gene bookmarking, is thought to be important for the ability of cells to express these genes during the following interphase. Previously, we reported a role for the DNA-binding protein heat shock factor (HSF2) in bookmarking the stress-inducible 70 OOO-Da heat shock protein (hsp70) gene. In this report, we have extended those studies and found that during mitosis, HSF2 is bound to the HSE promoter elements of other heat shock genes, including hsp90 and hsp27, as well as the proto-oncogene c-fos. The presence of HSF2 is important for expression of these genes because blocking HSF2 levels by RNA interference techniques leads to decreased levels of these proteins. These results suggest that HSF2 is important for constitutive as well as stress- inducible expression of HSE-containing genes.
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Identification of the PP2A-interacting region of heat shock transcription factor 2
Cell Stress & Chaperones, 2020Co-Authors: Hongyan Xing, Yiling Hong, Kevin D. SargeAbstract:Previous work in our laboratory demonstrated the existence of an association between heat shock transcription factor 2 (HSF2) and the serine/threonine phosphatase 2A, which is mediated by interaction between HSF2 and the A subunit (also called PR65) of this protein phosphatase. In light of the importance of HSF2-PP2A association for HSF2 cellular function, in this study, we have sought to dissect the sequences within HSF2 that are important for interaction with the A subunit of PP2A. The results of these experiments indicate that the HSF2 region comprising amino acids 343–363 is important for A subunit interaction. This region includes part of the C-terminal leucine zipper motif of HSF2 called heptad repeat C (HR-C). The results of transfection/immunoprecipitation experiments also show that deletion of the 6 amino acids from 343 to 348 from HSF2 (HSF2 (Δ343–348)), is sufficient to prevent HSF2 from interacting with PP2A. These data provide insight into a new functional domain of HSF2, the PP2A A subunit-interacting region.
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interaction of hsf1 and HSF2 with the hspa1b promoter in mouse epididymal spermatozoa
Biology of Reproduction, 2008Co-Authors: Donald C Wilkerson, Lynea A Murphy, Kevin D. SargeAbstract:The Hspa1b gene is one of the first genes expressed after fertilization, with expression observed in the male pronucleus as early as the one-cell stage of embryogenesis. This expression can occur in the absence of stress and is initiated during the minor zygotic genome activation. There is a significant reduction in the number of embryos developing to the blastocyte stage when HSPA1B levels are depleted, which supports the importance of this protein for embryonic viability. However, the mechanism responsible for allowing expression of Hspa1b during the minor zygotic genome activation (ZGA) is unknown. In this report, we investigated the role of HSF1 and HSF2 in bookmarking Hspa1b during late spermatogenesis. Western blot results show that both HSF1 and HSF2 are present in epididymal spermatozoa, and immunofluorescence analysis revealed that some of the HSF1 and HSF2 proteins in these cells overlap the 4′,6′-diamidino-2-phenylindole-stained DNA region. Results from chromatin immunoprecipitation assays showed that HSF1, HSF2, and SP1 are bound to the Hspa1b promoter in epididymal spermatozoa. Furthermore, we observed an increase in HSF2 binding to the Hspa1b promoter in late spermatids versus early spermatids, suggesting a likely period during spermatogenesis when transcription factor binding could occur. These results support a model in which the binding of HSF1, HSF2, and SP1 to the promoter of Hspa1b would allow the rapid formation of a transcription-competent state during the minor ZGA, thereby allowing Hspa1b expression.
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prc1 associates with the hsp70i promoter and interacts with HSF2 during mitosis
Experimental Cell Research, 2008Co-Authors: Lynea A Murphy, Donald C Wilkerson, Yiling Hong, Kevin D. SargeAbstract:Mitosis is a series of events leading to division of a cell by the process known as cytokinesis. Protein regulating cytokinesis 1 (PRC1) is a CDK substrate that associates with the mitotic spindle and functions in microtubule bundling. Previous studies revealed that loss of PRC1 is associated with chromosomal mis-segregation and atypical chromosome alignment. HSF2 is a DNA binding protein that we previously showed bookmarks the hsp70i gene during mitosis, an epigenetic mechanism which allows the hsp70i gene to re-establish transcriptional competence early in G1. Another study demonstrated that HSF2−/− mouse embryonic fibroblasts (MEFs) exhibit increased numbers of multinucleated cells vs. wild-type MEFs. This suggests that HSF2 is important for proper cytokinesis, but the mechanism was unknown. Here we report the existence of a direct interaction between HSF2 and PRC1. HSF2 and PRC1 associate during mitosis and co-localize during this phase of the cell cycle. PRC1 does not interact with the related protein HSF1, indicating the specificity of the HSF2-PRC1 interaction. Intriguingly, PRC1 is associated with the hsp70i promoter during mitosis. These results provide a potential mechanistic basis for the defective cytokinesis phenotype exhibited by HSF2−/− cells, as well as suggest a potential role for PRC1 in HSF2-mediated gene bookmarking.
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mel 18 interacts with HSF2 and the sumo e2 ubc9 to inhibit HSF2 sumoylation
Journal of Biological Chemistry, 2008Co-Authors: Jie Zhang, Michael L. Goodson, Yiling Hong, Kevin D. SargeAbstract:In a previous study we found that sumoylation of the DNA-binding protein heat shock factor 2 (HSF2) is up-regulated during mitosis, but the mechanism that mediates this regulation was unknown. Here we show that HSF2 interacts with the polycomb protein MEL-18, that this interaction decreases during mitosis, and that overexpression and RNA interference-mediated reduction of MEL-18 result in decreased and increased HSF2 sumoylation, respectively. Other results suggest that MEL-18 may also function to inhibit the sumoylation of other cellular proteins. The results also show that MEL-18 is able to interact with the small ubiquitin-like modifier (SUMO) ubiquitin carrier protein (E2) enzyme UBC9 and that MEL-18 inhibits the ability of UBC9 to transfer the SUMO protein to target proteins. Together, the results in this work suggest a mechanism in which MEL-18 bound to HSF2 inhibits its sumoylation by binding to and inhibiting the activity of UBC9 enzymes in the vicinity of HSF2. These results provide an explanation for how mitotic HSF2 sumoylation is regulated and suggest that MEL-18, in contrast to the sumoylation-stimulating activities of the polycomb protein PC2, actually functions like an anti-SUMO ubiquitin-protein isopeptide ligase (E3), interacting both with HSF2 and the SUMO E2 UBC9 but acting to inhibit UBC9 activity to decrease sumoylation of a target protein, in this case that of HSF2.
Richard I. Morimoto - One of the best experts on this subject based on the ideXlab platform.
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Heat shock factors: integrators of cell stress, development and lifespan
Nature Reviews Molecular Cell Biology, 2010Co-Authors: Malin Åkerfelt, Richard I. Morimoto, Lea SistonenAbstract:Heat shock factors (HSFs) are essential for all organisms to survive exposures to acute stress. They are best known as inducible transcriptional regulators of genes encoding molecular chaperones and other stress proteins. Four members of the HSF family are also important for normal development and lifespan-enhancing pathways, and the repertoire of HSF targets has thus expanded well beyond the heat shock genes. These unexpected observations have uncovered complex layers of post-translational regulation of HSFs that integrate the metabolic state of the cell with stress biology, and in doing so control fundamental aspects of the health of the proteome and ageing. Heat shock factors (HSFs) are essential for all organisms to survive exposures to stress, as they bind heat shock elements to induce transcription of heat shock proteins (HSPs). In addition, the HSFs are important regulators involved in development, lifespan and disease, thereby integrating pathways of stress responses and normal physiology. The mammalian HSF family consists of four members: HSF1, HSF2, HSF3 and HSF4. Distinct HSFs possess unique and overlapping functions, with a great variation in expression patterns, post-translational modifications (PTMs) and interacting protein partners. HSFs are composed of functional domains, of which the DNA-binding domain is best preserved. The HSF1 activation–attenuation cycle involves trimerization, strict regulation by multiple PTMs, such as acetylation, phosphorylation and sumoylation, and feedback from HSPs. Functional crosstalk between HSF family members facilitates the fine-tuning of HSF-mediated gene regulation. HSF-knockout mouse models have made it possible to identify many targets, which have further extended the impact of HSFs in developmental processes, such as oogenesis, corticogenesis and spermatogenesis. The ability to sense and respond to environmental challenges is important for lifespan, and HSF1 is a longevity factor that prevents global instability of the proteome during ageing. The life-promoting function of HSF1 is strictly controlled by the insulin and insulin-like signalling pathway in Caenorhabditis elegans . HSF1 is a potent modifier of tumorigenesis and HSF1 deficiency in mice counteracts tumour initiation and progression. HSF1 is therefore a potential cancer drug target. As many human, age-related pathologies are associated with stress and misfolded proteins, several small-molecule activators and inhibitors of HSFs could be used for pharmacologic modulation of HSF-mediated gene regulation. Heat shock factors (HSFs) are essential for survival in a stressful environment. HSFs mediate the heat shock response by binding heat shock elements present in heat shock protein (HSP) genes, thereby mediating their transcription. They are also important regulators of development, lifespan and disease.
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Stress-Specific Activation and Repression of Heat Shock Factors 1 and 2
Molecular and Cellular Biology, 2001Co-Authors: Anu Mathew, Sameer K. Mathur, Caroline Jolly, Richard I. MorimotoAbstract:Vertebrate cells express a family of heat shock transcription factors (HSF1 to HSF4) that coordinate the inducible regulation of heat shock genes in response to diverse signals. HSF1 is potent and activated rapidly though transiently by heat shock, whereas HSF2 is a less active transcriptional regulator but can retain its DNA binding properties for extended periods. Consequently, the differential activation of HSF1 and HSF2 by various stresses may be critical for cells to survive repeated and diverse stress challenges and to provide a mechanism for more precise regulation of heat shock gene expression. Here we show, using a novel DNA binding and detection assay, that HSF1 and HSF2 are coactivated to different levels in response to a range of conditions that cause cell stress. Above a low basal activity of both HSFs, heat shock preferentially activates HSF1, whereas the amino acid analogue azetidine or the proteasome inhibitor MG132 coactivates both HSFs to different levels and hemin preferentially induces HSF2. Unexpectedly, we also found that heat shock has dramatic adverse effects on HSF2 that lead to its reversible inactivation coincident with relocalization from the nucleus. The reversible inactivation of HSF2 is specific to heat shock and does not occur with other stressors or in cells expressing high levels of heat shock proteins. These results reveal that HSF2 activity is negatively regulated by heat and suggest a role for heat shock proteins in the positive regulation of HSF2.
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heat shock response and protein degradation regulation of HSF2 by the ubiquitin proteasome pathway
Molecular and Cellular Biology, 1998Co-Authors: Anu Mathew, Sameer K. Mathur, Richard I. MorimotoAbstract:Mammalian cells coexpress a family of heat shock factors (HSFs) whose activities are regulated by diverse stress conditions to coordinate the inducible expression of heat shock genes. Distinct from HSF1, which is expressed ubiquitously and activated by heat shock and other stresses that result in the appearance of nonnative proteins, the stress signal for HSF2 has not been identified. HSF2 activity has been associated with development and differentiation, and the activation properties of HSF2 have been characterized in hemintreated human K562 erythroleukemia cells. Here, we demonstrate that a stress signal for HSF2 activation occurs when the ubiquitin-proteasome pathway is inhibited. HSF2 DNA-binding activity is induced upon exposure of mammalian cells to the proteasome inhibitors hemin, MG132, and lactacystin, and in the mouse ts85 cell line, which carries a temperature sensitivity mutation in the ubiquitin-activating enzyme (E1) upon shift to the nonpermissive temperature. HSF2 is labile, and its activation requires both continued protein synthesis and reduced degradation. The downstream effect of HSF2 activation by proteasome inhibitors is the induction of the same set of heat shock genes that are induced during heat shock by HSF1, thus revealing that HSF2 affords the cell with a novel heat shock gene-regulatory mechanism to respond to changes in the protein-degradative machinery.
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Function and regulation of heat shock factor 2 during mouse embryogenesis
Proceedings of the National Academy of Sciences of the United States of America, 1997Co-Authors: M. Rallu, Richard I. Morimoto, Michel Morange, M. T. Loones, Y. Lallemand, V. MezgerAbstract:The spontaneous expression of heat shock genes during development is well documented in many animal species, but the mechanisms responsible for this developmental regulation are only poorly understood. In vertebrates, additional heat shock transcription factors, distinct from the heat shock factor 1 (HSF1) involved in the stress response, were suggested to be involved in this developmental control. In particular, the mouse HSF2 has been found to be active in testis and during preimplantation development. However, the role of HSF2 and its mechanism of activation have remained elusive due to the paucity of data on its expression during development. In this study, we have examined HSF2 expression during the postimplantation phase of mouse development. Our data show a developmental regulation of HSF2, which is expressed at least until 15.5 days of embryogenesis. It becomes restricted to the central nervous system during the second half of gestation. It is expressed in the ventricular layer of the neural tube which contains mitotically active cells but not in postmitotic neurons. Parallel results were obtained for mRNA, protein, and activity levels, demonstrating that the main level of control was transcriptional. The detailed analysis of the activity of a luciferase reporter gene under the control of the hsp70.1 promoter, as well as the description of the protein expression patterns of the major heat shock proteins in the central nervous system, show that HSF2 and heat shock protein expression domains do not coincide. This result suggests that HFS2 might be involved in other regulatory developmental pathways and paves the way to new functional approaches.
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Regulatory differences in the stress response of hippocampal neurons and glial cells after heat shock
The Journal of Neuroscience, 1996Co-Authors: Charles J. Marcuccilli, Richard I. Morimoto, Sameer K. Mathur, Richard J. MillerAbstract:During periods of stress, cells depend on a transient, highly conserved, and regulated response to maintain homeostasis. This "heat shock response" is mediated transcriptionally by a multigene family of heat shock factors (HSF). The presence of multiple HSF suggests that activation of a given HSF is stress-specific. Using Western blot analysis, we have demonstrated the inability of primary cultured rat hippocampal neurons to induce a heat shock response after hyperthermia. In contrast, secondary cultured rat glial cells demonstrated a robust response. Examination of whole-cell extracts from the two cell types with gel shift mobility analysis and Western blot analysis revealed that although glial cells express HSF1 and HSF2, hippocampal neurons only express HSF2. Incubation of whole-cell extracts with monoclonal antisera raised against HSF1 and HSF2 before gel shift mobility analysis demonstrated HSF1 DNA-binding activity in glial cells and HSF2 DNA-binding activity in neurons. HSF1 has been shown to be the principal mediator of heat-induced heat shock gene expression. These results suggest that the deficient heat shock response of hippocampal neurons at this developmental stage is attributable to a lack of HSF1 expression. Furthermore, these results suggest that considerations of selective neuronal vulnerability to environmental stress should include the principal mediators of the stress response, the HSF.
Viswanadha Vijaya Padma - One of the best experts on this subject based on the ideXlab platform.
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data supporting the angiotensin ii activates mel18 to desumoylate HSF2 for hypertension related heart failure
Data in Brief, 2018Co-Authors: Chih Yang Huang, Tsung Jung Ho, Ray Jade Chen, Fuu Jen Tsai, Viswanadha Vijaya PadmaAbstract:Abstract In association with the published article “Inhibition of HSF2 SUMOylation via MEL18 upregulates IGF-IIR and leads to hypertension-induced cardiac hypertrophy” (Huang et al., 2017) [1] , this data article contains information about deSUMOylation of HSF2 on lysine 82 on angiotensin II (ANG II) -induced cardiac hypertrophy, which is mediated by MEL18. Isolated adult human whole heart tissue showed MEL18-mediated HSF2-IGF-IIR pathway is upregulated in hypertension human heart, compared to health human heart.
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inhibition of HSF2 sumoylation via mel18 upregulates igf iir and leads to hypertension induced cardiac hypertrophy
International Journal of Cardiology, 2017Co-Authors: Chih Yang Huang, Tsung Jung Ho, Ray Jade Chen, Fuu Jen Tsai, Viswanadha Vijaya PadmaAbstract:Abstract Cardiac hypertrophy is a major characteristic of early-stage hypertension-related heart failure. We have found that the insulin-like growth factor receptor II (IGF-IIR) signaling was critical for hypertensive angiotensin II-induced cardiomyocyte hypertrophy and apoptosis. Moreover, this IGF-IIR signaling was elegantly modulated by the heat shock transcription factors (HSFs) during heart failure. However, the detailed mechanism by which HSFs regulates IGF-IIR during hypertension-induced cardiac hypertrophy remains elusive. In this study, we found that heat shock transcription factor 2 (HSF2) activated IGF-IIR to induce cardiac hypertrophy for hypertension-induced heart failure. The transcriptional activity of HSF2 appeared to be primarily mediated by SUMOylation via conjugation with small ubiquitin-like modifier-1 (SUMO-1). The SUMOylation of HSF2 was severely attenuated by MEL18 (also known as polycomb group ring finger 2 or PCGF2) in the heart of spontaneously hypertensive rats (SHR). Inhibition of HSF2 SUMOylation severely induced cardiac hypertrophy via IGF-IIR-mediated signaling in hypertensive rats. Angiotensin II receptor type I blocker (ARB) treatment in spontaneously hypertensive rats restored HSF2 SUMOylation and alleviated the cardiac defects. Thus, our study uncovered a novel MEL18-SUMO-1-HSF2-IGF-IIR pathway in the heart that profoundly influences cardiac hypertrophy for hypertension-induced heart failure.
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p53 mediated mir 18 repression activates HSF2 for igf iir dependent myocyte hypertrophy in hypertension induced heart failure
Cell Death and Disease, 2017Co-Authors: Chih Yang Huang, Tsung Jung Ho, Fu Jen Tsai, Viswanadha Vijaya PadmaAbstract:Hypertension-induced cardiac hypertrophy and attenuated cardiac function are the major characteristics of early stage heart failure. Cardiomyocyte death in pathological cardiac conditions is the primary cause of heart failure and mortality. Our previous studies found that heat shock factor 1 (HSF1) protected cardiomyocytes from death by suppressing the IGF-IIR signaling pathway, which is critical for hypertensive angiotensin II-induced cardiomyocyte apoptosis. However, the role of heat shock factor 2 (HSF2) in hypertension-induced cardiac hypertrophy is unknown. We identified HSF2 as a miR-18 target for cardiac hypertrophy. p53 activation in angiotensin II (ANG II)-stimulated NRVMs is responsible for miR-18 downregulation both in vitro and in vivo, which triggers HSF2 expression and the activation of IGF-IIR-induced cardiomyocyte hypertrophy. Finally, we provide genetic evidence that miR-18 is required for cardiomyocyte functions in the heart based on the gene transfer of cardiac-specific miR-18 via adenovirus-associated virus 2 (AAV2). Transgenic overexpression of miR-18 in cardiomyocytes is sufficient to protect against dilated cardiomyopathy during hypertension-induced heart failure. Our results demonstrated that the p53-miR-18-HSF2-IGF-IIR axis was a critical regulatory pathway of cardiomyocyte hypertrophy in vitro and in vivo, suggesting that miR-18 could be a therapeutic target for the control of cardiac functions and the alleviation of cardiomyopathy during hypertension-induced heart failure.
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Mitochondrial ROS-induced ERK1/2 activation and HSF2-mediated AT1R upregulation are required for doxorubicin-induced cardiotoxicity
Journal of Cellular Physiology, 2017Co-Authors: Chih Yang Huang, Jia Yi Chen, Tsung Jung Ho, Tung Sheng Chen, Fu Jen Tsai, Viswanadha Vijaya PadmaAbstract:Doxorubicin (DOX), one useful chemotherapeutic agent, is limited in clinical use because of its serious cardiotoxicity. Growing evidence suggests that angiotensin receptor blockers (ARBs) have cardioprotective effects in DOX-induced cardiomyopathy. However, the detailed mechanisms underlying the action of ARBs on the prevention of DOX-induced cardiomyocyte cell death have yet to be investigated. Our results showed that angiotensin II receptor type I (AT1 R) plays a critical role in DOX-induced cardiomyocyte apoptosis. We found that MAPK signaling pathways, especially ERK1/2, participated in modulating AT1 R gene expression through DOX-induced mitochondrial ROS release. These results showed that several potential heat shock binding elements (HSE), which can be recognized by heat shock factors (HSFs), located at the AT1 R promoter region. HSF2 markedly translocated from the cytoplasm to the nucleus when cardiomyocytes were damaged by DOX. Furthermore, the DNA binding activity of HSF2 was enhanced by DOX via deSUMOylation. Overexpression of HSF2 enhanced DOX-induced cardiomyocyte cell death as well. Taken together, we found that DOX induced mitochondrial ROS release to activate ERK-mediated HSF2 nuclear translocation and AT1 R upregulation causing DOX-damaged heart failure in vitro and in vivo.
Junghoon Yoon - One of the best experts on this subject based on the ideXlab platform.
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heat shock factor 4a hsf4a represses HSF2 expression and HSF2 mediated transcriptional activity
Journal of Cellular Physiology, 2012Co-Authors: Junghoon YoonAbstract:Heat shock factors (HSFs) are the main transcriptional regulators of the stress-induced expression of heat shock protein genes. HSF2, which is one of the HSFs, is activated during differentiation and development but it is unclear how they regulate during cellular processes. Here, we examined the role of HSF4a on the regulation of HSF2 in HEK 293 cells. We found that HSF2 levels are negatively correlated with HSF4a expression and that overexpression of HSF4a reduces hemin-induced HSF2 mRNA and protein levels. Moreover, hemin-induced activation of HSF2 was also markedly inhibited in HSF4a expressed cells. Immunoprecipitation assay showed that HSF2 binds to the oligomerization domain of HSF4a. Hemin treatment inhibited their interaction and induced localization of HSF2 and HSF4a in nuclear. In addition, we found that HSF4a or HSF4a DNA binding domain (117 aa) inhibited the activity of hemin-induced HSP70 promoter. Consequently, HSF4a inhibits HSF2 expression or transcriptional activity through negative regulation of HSF2 binding to the HSP70 promoter. In summary, our findings suggest novel mechanisms of HSF2 regulation controlled by HSF4a. J. Cell. Physiol. 227: 1–6, 2012. © 2011 Wiley Periodicals, Inc.
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Heat shock factor 4a (HSF4a) represses HSF2 expression and HSF2‐mediated transcriptional activity
Journal of Cellular Physiology, 2011Co-Authors: Junghoon YoonAbstract:Heat shock factors (HSFs) are the main transcriptional regulators of the stress-induced expression of heat shock protein genes. HSF2, which is one of the HSFs, is activated during differentiation and development but it is unclear how they regulate during cellular processes. Here, we examined the role of HSF4a on the regulation of HSF2 in HEK 293 cells. We found that HSF2 levels are negatively correlated with HSF4a expression and that overexpression of HSF4a reduces hemin-induced HSF2 mRNA and protein levels. Moreover, hemin-induced activation of HSF2 was also markedly inhibited in HSF4a expressed cells. Immunoprecipitation assay showed that HSF2 binds to the oligomerization domain of HSF4a. Hemin treatment inhibited their interaction and induced localization of HSF2 and HSF4a in nuclear. In addition, we found that HSF4a or HSF4a DNA binding domain (117 aa) inhibited the activity of hemin-induced HSP70 promoter. Consequently, HSF4a inhibits HSF2 expression or transcriptional activity through negative regulation of HSF2 binding to the HSP70 promoter. In summary, our findings suggest novel mechanisms of HSF2 regulation controlled by HSF4a. J. Cell. Physiol. 227: 1–6, 2012. © 2011 Wiley Periodicals, Inc.