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1.
Int J Mol Sci ; 25(3)2024 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-38339104

RESUMO

One of the extracellular matrix proteins, tenascin-C (TN-C), is known to be upregulated in age-related inflammatory diseases such as cancer and cardiovascular diseases. Expression of this molecule is frequently detected, especially in the macrophage-rich areas of atherosclerotic lesions; however, the role of TN-C in mechanisms underlying the progression of atherosclerosis remains obscure. Previously, we found a hidden bioactive sequence termed TNIIIA2 in the TN-C molecule and reported that the exposure of this sequence would be carried out through limited digestion of TN-C by inflammatory proteases. Thus, we hypothesized that some pro-atherosclerotic phenotypes might be elicited from macrophages when they were stimulated by TNIIIA2. In this study, TNIIIA2 showed the ability to accelerate intracellular lipid accumulation in macrophages. In this experimental condition, an elevation of phagocytic activity was observed, accompanied by a decrease in the expression of transporters responsible for lipid efflux. All these observations were mediated through the induction of excessive ß1-integrin activation, which is a characteristic property of the TNIIIA2 sequence. Finally, we demonstrated that the injection of a drug that targets TNIIIA2's bioactivity could rescue mice from atherosclerotic plaque expansion. From these observations, it was shown that TN-C works as a pro-atherosclerotic molecule through an internal TNIIIA2 sequence. The possible advantages of clinical strategies targeting TNIIIA2 are also indicated.


Assuntos
Aterosclerose , Células Espumosas , Placa Aterosclerótica , Animais , Camundongos , Proteínas da Matriz Extracelular , Fibronectinas/metabolismo , Células Espumosas/metabolismo , Lipídeos , Peptídeos/química , Tenascina/metabolismo
2.
Genes Cells ; 27(12): 719-730, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36203316

RESUMO

The induction mechanism of heme oxygenase-1 (HO-1) by heat shock (HS) is still unknown. Here, we discovered that HS activates the HO-1 expression in a mouse hepatoma cell line (Hepa 1-6). Knockdown experiments showed that the HS-induced HO-1 expression was dependent on HS factor 1 (HSF1). A chromatin immunoprecipitation (ChIP) assay demonstrated that the HS-activated HSF1 bound to the HS elements (HSEs) in the upstream enhancer 1 region (E1). Unexpectedly, HS also facilitates the BTB and CNC homology 1 (BACH1) binding to the Maf recognition elements (MAREs) in E1. We examined the effects of a catalytically inactive CRISPR-associated 9 nucleases (dCas9) with short guide RNAs (sgRNAs), and demonstrated that the HSF1 binding to HSEs in E1 was indispensable for the HS-induced HO-1 expression. Heme treatment (HA) dissociates BACH1 from MAREs and facilitated the binding of nuclear factor-erythroid-2-related factor 2 (NRF2) to MAREs. Following treatment with both HS and HA, the HO-1 induction and the HSF1 binding to HSEs in E1 were most notably observed. These results indicate that the HS-induced HO-1 expression is dependent on the HSF1 binding to HSEs in E1, although modulated by the BACH1 and NRF2 binding to MAREs within the same E1.


Assuntos
Resposta ao Choque Térmico , Heme Oxigenase-1 , Animais , Camundongos , Heme Oxigenase-1/genética , Linhagem Celular , Fatores de Transcrição de Zíper de Leucina Básica/genética , Fatores de Transcrição de Choque Térmico/genética
3.
Biochem Biophys Res Commun ; 506(1): 7-11, 2018 11 17.
Artigo em Inglês | MEDLINE | ID: mdl-30316516

RESUMO

Heme oxygenase-1 (HO-1) is an inducible enzyme responding to various stresses and has cytoprotective activities. Although HO-1 has been referred to as heat shock protein (HSP) 32, the heat-mediated induction of HO-1 varies among different species and cell lines. We examined the effects of heat shock on HO-1 expression in mouse embryonic fibroblast (MEF) cells deficient in heat shock factor 1 (HSF1) or nuclear factor-erythroid-2-related factor 2 (NRF2). Heme-induced expression of HO-1 was 2-fold higher in Hsf1-/- cells than in the wild-type cells at both mRNA and protein levels. In Nrf2-/- cells, heme-induced expression of HO-1 was not detected. In contrast, HO-1 expression was markedly induced by heat shock at 40-42 °C in Nrf2-/- cells while the wild-type cells were not responsive. The heat-induced expression of HO-1 in Nrf2-/- cells were almost completely diminished by transfection of siRNA against Hsf1 gene. These results suggest that HSF1 and NRF2 suppress heme-induced and heat-induced HO-1 expression, respectively.


Assuntos
Fibroblastos/metabolismo , Fatores de Transcrição de Choque Térmico/genética , Resposta ao Choque Térmico/genética , Heme Oxigenase-1/genética , Proteínas de Membrana/genética , Fator 2 Relacionado a NF-E2/genética , Animais , Linhagem Celular Transformada , Embrião de Mamíferos , Fibroblastos/citologia , Regulação da Expressão Gênica , Fatores de Transcrição de Choque Térmico/antagonistas & inibidores , Fatores de Transcrição de Choque Térmico/deficiência , Heme Oxigenase-1/metabolismo , Proteínas de Membrana/metabolismo , Camundongos , Fator 2 Relacionado a NF-E2/deficiência , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Transdução de Sinais
4.
IUBMB Life ; 69(4): 246-254, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28294521

RESUMO

Human antioxidant protein 1 (Atox1) plays a crucial role in cellular copper homeostasis. Atox1 captures cytosolic copper for subsequent transfer to copper pumps in trans Golgi network, thereby facilitating copper supply to various copper-dependent oxidereductases matured within the secretory vesicles. Atox1 and other copper chaperones handle cytosolic copper using Cys thiols which are ideal ligands for coordinating Cu(I). Recent studies demonstrated reversible oxidation of these Cys residues in copper chaperones, linking cellular redox state to copper homeostasis. Highlighted in this review are unique redox properties of Atox1 and other copper chaperones. Also, summarized are the redox nodes in the cytosol which potentially play dominant roles in the redox regulation of copper chaperones. © 2016 IUBMB Life, 69(4):246-254, 2017.


Assuntos
Proteínas de Transporte de Cátions/metabolismo , Cobre/metabolismo , Metalochaperonas/metabolismo , Proteínas de Transporte de Cátions/genética , Proteínas de Transporte de Cobre , Citosol/metabolismo , Humanos , Metalochaperonas/genética , Chaperonas Moleculares/metabolismo , Compostos de Sulfidrila/metabolismo
5.
Biol Pharm Bull ; 39(6): 1007-12, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27251503

RESUMO

In this study we investigated the effect of free heme, the local level of which was increased by bleeding, on the intestinal barrier function, using human epithelial colorectal adenocarcinoma cells (Caco-2). Our results show that the addition of hemin to the culture medium markedly disrupted the barrier function, which was significantly improved by glutamine supplementation. Although hemin treatment caused the increased expression of heme oxygenase (HO)-1, the inhibition of HO activity resulted in the aggravation of hemin-induced barrier dysfunction. Up-regulation of HO-1 by pretreatment with a low concentration of hemin almost completely prevented hemin-induced barrier dysfunction. Taken together, these observations indicate that an abnormally high level of intracellular free heme causes barrier dysfunction, probably through the modulation of proteins forming tight junctions.


Assuntos
Hemorragia Gastrointestinal/metabolismo , Heme Oxigenase-1/metabolismo , Mucosa Intestinal/metabolismo , Ácido Ascórbico/farmacologia , Células CACO-2 , Glutamina/farmacologia , Heme Oxigenase-1/antagonistas & inibidores , Hemina/farmacologia , Humanos , Malondialdeído/metabolismo , Metaloporfirinas/farmacologia
6.
Pharmacology ; 91(1-2): 104-11, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23328693

RESUMO

In this study, we investigated the protective effect of glutamine on barrier dysfunction induced by ethanol, by using human epithelial colorectal adenocarcinoma cells (Caco-2). Our results show that addition of glutamine to culture medium significantly improved the disruption of integrity caused by ethanol, which was associated with increased expression of heat shock protein 70 (Hsp70). Ethanol exposure moderately activates heat shock factor 1 (HSF1), which was characterized by increased DNA-binding activity and phosphorylation status of HSF1. Remarkably, glutamine treatment enhanced ethanol-mediated expression of Hsp70 and activation of HSF1. Up-regulation of Hsp70 by pretreatment with heat stress also promoted recovery from the ethanol-induced barrier dysfunction. Taken together, these observations indicate that glutamine protects the intestinal barrier function in Caco-2 cells, in part by modulating HSF1-mediated Hsp70 expression.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Células Epiteliais/efeitos dos fármacos , Glutamina/farmacologia , Proteínas de Choque Térmico HSP70/metabolismo , Fatores de Transcrição/metabolismo , Células CACO-2 , Colo , Células Epiteliais/metabolismo , Etanol , Fatores de Transcrição de Choque Térmico , Humanos , Inulina/metabolismo , Proteína da Zônula de Oclusão-1/metabolismo
7.
J Immunol ; 184(2): 1041-8, 2010 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-20018623

RESUMO

The febrile response is a complex physiological reaction to disease, including a cytokine-mediated increase in body temperature and the activation of inflammatory systems. Fever has beneficial roles in terms of disease prognosis, partly by suppressing the expression of inflammatory cytokines. However, the molecular mechanisms underlining the fever-mediated suppression of inflammatory gene expression have not been clarified. In this study, we showed that heat shock suppresses LPS-induced expression of IL-6, a major pyrogenic cytokine, in mouse embryonic fibroblasts and macrophages. Heat shock transcription factor 1 (HSF1) activated by heat shock induced the expression of activating transcription factor (ATF) 3, a negative regulator of IL-6, and ATF3 was necessary for heat-mediated suppression of IL-6, indicating a fever-mediated feedback loop consisting of HSF1 and ATF3. A comprehensive analysis of inflammatory gene expression revealed that heat pretreatment suppresses LPS-induced expression of most genes (86%), in part (67%) via ATF3. When HSF1-null and ATF3-null mice were injected with LPS, they expressed much higher levels of IL-6 than wild-type mice, resulting in an exaggerated febrile response. These results demonstrate a novel inhibitory pathway for inflammatory cytokines.


Assuntos
Fator 3 Ativador da Transcrição/fisiologia , Proteínas de Ligação a DNA/fisiologia , Regulação da Expressão Gênica/imunologia , Resposta ao Choque Térmico/imunologia , Interleucina-6/antagonistas & inibidores , Fatores de Transcrição/fisiologia , Fator 3 Ativador da Transcrição/genética , Animais , Retroalimentação Fisiológica , Febre , Fibroblastos/imunologia , Fibroblastos/metabolismo , Fatores de Transcrição de Choque Térmico , Interleucina-6/genética , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Proteínas Repressoras
8.
J Biochem ; 170(4): 501-510, 2021 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-34061198

RESUMO

The mechanism of heme oxygenase-1 (HO-1) induction by heat shock (HS) loading remains unclear. Here, we investigated the contribution of transcription factors to HS-induced HO-1 expression, using a rat hepatoma cell line (H-4-II-E). Our results demonstrated that HS treatment resulted in a marked induction of HO-1. Immunohistochemical analysis showed a slight mismatch in the expression levels of HO-1 and HSP70 by HS among cells, suggesting a conflict between multiple induction mechanisms. We observed HS-induced nuclear localization of, not only phosphorylated HSF1 but also NRF2, which is a typical transcription factor activated by oxidative stress. HSF1 knockdown in H-4-II-E markedly reduced HO-1 induction by HS, while NRF2 knockdown resulted in a partial effect. The chromatin immunoprecipitation assay demonstrated that HS loading resulted in significant binding of HSF1 to the HSE in the promoter proximal region of HO-1 gene and another HSE located close to the Maf recognition element (MARE) in the -4 kb upstream enhancer region 1, where NRF2 also bound, together with basic leucine zipper transcription factor 1, a negative transcription factor of HO-1. These observations indicate that HO-1 induction by HS is mainly mediated by HSF1 binding to the proximal HSE. NRF2 binding to MARE by HS is predominantly suppressed by an increased binding of BACH1.


Assuntos
Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Carcinoma Hepatocelular/metabolismo , Fatores de Transcrição de Choque Térmico/metabolismo , Heme Oxigenase-1/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Proteínas Repressoras/metabolismo , Animais , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Núcleo Celular/metabolismo , Imunoprecipitação da Cromatina/métodos , Resposta ao Choque Térmico , Heme Oxigenase-1/genética , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Estresse Oxidativo , Regiões Promotoras Genéticas , Ligação Proteica , Ratos
9.
Antioxidants (Basel) ; 9(2)2020 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-32028573

RESUMO

Glutathione is a small thiol-containing peptide that plays a central role in maintaining cellular redox homeostasis. Glutathione serves as a physiologic redox buffer by providing thiol electrons for catabolizing harmful oxidants and reversing oxidative effects on biomolecules. Recent evidence suggests that the balance of reduced and oxidized glutathione (GSH/GSSG) defines the redox states of Cys residues in proteins and fine-tunes their stabilities and functions. To elucidate the redox balance of cellular glutathione at subcellular resolution, a number of redox-sensitive green fluorescent protein (roGFP) variants have been developed. In this study, we constructed and functionally validated organelle- and cytoskeleton-targeted roGFP and elucidated the redox status of the cytosolic glutathione at a subcellular resolution. These new redox sensors firmly established a highly reduced redox equilibrium of cytosolic glutathione, wherein significant deviation was observed among cells. By targeting the sensor to the cytosolic and lumen sides of the Golgi membrane, we identified a prominent redox gradient across the biological membrane at the Golgi body. The results demonstrated that organelle- and cytoskeleton-targeted sensors enable the assessment of glutathione oxidation near the cytosolic surfaces of different organelle membranes.

10.
Brain Res ; 1212: 9-17, 2008 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-18445491

RESUMO

Mechanisms of age-related hearing loss (ARHL) have not been elucidated as aging processes are extremely complex. Although oxidative stress and apoptotic cell death are involved in progression of ARHL, number of trial to treat ARHL is limited. Heat shock response is characterized by induction of heat shock proteins (HSPs) in response to stresses such as heat shock, which diminishes during aging. HSPs act as molecular chaperones, and some HSPs also inhibit apoptotic pathways. Here, we examined age-related expression of HSPs in the cochlea of ARHL model DBA/2J mice and control CBA/N mice. Western blot assay revealed that CBA/N mice showed constant expression of Hsp70 and Hsp110 with age, but not in DBA/2J mice. The result suggests that pharmacological upregulation of HSPs might attenuate ARHL. We administered DBA/2J mice with food containing geranylgeranylacetone (GGA) that induces HSPs in the cochlea, and found that its administration suppresses ARHL examined by ABR test and histological examination though protection is specific for the apical part of the cochlea. These results demonstrate that dietary supplementation of GGA could be an effective therapeutic strategy for treatment of ARHL.


Assuntos
Envelhecimento , Antiulcerosos/administração & dosagem , Diterpenos/administração & dosagem , Presbiacusia/tratamento farmacológico , Animais , Encéfalo/metabolismo , Contagem de Células , Cóclea/metabolismo , Cóclea/patologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Potenciais Evocados Auditivos do Tronco Encefálico/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Proteínas de Choque Térmico HSP110/metabolismo , Proteínas de Choque Térmico HSP70/metabolismo , Células Ciliadas Auditivas/patologia , Masculino , Camundongos , Camundongos Endogâmicos DBA , Presbiacusia/patologia , Presbiacusia/fisiopatologia , Psicofísica
11.
Redox Biol ; 14: 679-685, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29179107

RESUMO

Production of reactive oxygen species (ROS) and consequent glutathione oxidation are associated with various physiological processes and diseases, including cell differentiation, senescence, and inflammation. GFP-based redox sensors provide a straight-forward approach to monitor ROS levels and glutathione oxidation within a living cell at the subcellular resolution. We utilized palmitoylated versions of cytosolic glutathione and hydrogen peroxide sensors (Grx1-roGFP2 and roGFP2-Orp1, respectively) and demonstrated a unique redox environment near biological membranes. In HeLa cells, cytosolic glutathione was practically completely reduced (EGSH/GSSG = - 333mV) and hydrogen peroxide level was under the detectable range. In contrast, the cytoplasmic milieu near membranes of intracellular vesicles exhibited significant glutathione oxidation (EGSH/GSSG > - 256mV) and relatively high H2O2 production, which was not observed for the plasma membrane. These vesicles colocalized with internalized EGFR, suggesting that H2O2 production and glutathione oxidation are characteristics of cytoplasmic surfaces of the endocytosed vesicles. The results visually illustrate local redox heterogeneity within the cytosol for the first time.


Assuntos
Membrana Celular/metabolismo , Glutationa/metabolismo , Proteínas de Fluorescência Verde/metabolismo , Peróxido de Hidrogênio/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Técnicas Biossensoriais , Citoplasma/metabolismo , Ácidos Graxos Monoinsaturados/metabolismo , Células HeLa , Humanos , Imagem Óptica , Oxirredução
12.
Mol Cell Biol ; 23(16): 5882-95, 2003 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-12897157

RESUMO

Heat shock response, which is characterized by the induction of a set of heat shock proteins, is essential for induced thermotolerance and is regulated by heat shock transcription factors (HSFs). Curiously, HSF1 is essential for heat shock response in mammals, whereas in avian HSF3, an avian-specific factor is required for the burst activation of heat shock genes. Amino acid sequences of chicken HSF1 are highly conserved with human HSF1, but those of HSF3 diverge significantly. Here, we demonstrated that chicken HSF1 lost the ability to activate heat shock genes through the amino-terminal domain containing an alanine-rich sequence and a DNA-binding domain. Surprisingly, chicken and human HSF1 but not HSF3 possess a novel function that protects against a single exposure to mild heat shock, which is not mediated through the activation of heat shock genes. Overexpression of HSF1 mutants that could not bind to DNA did not restore the susceptibility to cell death in HSF1-null cells, suggesting that the new protective role of HSF1 is mediated through regulation of unknown target genes other than heat shock genes. These results uncover a novel role of vertebrate HSF1, which has been masked under the roles of heat shock proteins.


Assuntos
Proteínas Aviárias , Morte Celular , Proteínas de Ligação a DNA/metabolismo , Proteínas de Ligação a DNA/fisiologia , Proteínas de Choque Térmico , Transativadores/fisiologia , Adenoviridae/genética , Alanina/química , Sequência de Aminoácidos , Animais , Northern Blotting , Linhagem Celular , Galinhas , Cromatografia em Gel , DNA/metabolismo , DNA Complementar/metabolismo , Deleção de Genes , Fatores de Transcrição de Choque Térmico , Humanos , Modelos Genéticos , Dados de Sequência Molecular , Mutação , Filogenia , Ligação Proteica , Estrutura Terciária de Proteína , Frações Subcelulares , Temperatura , Fatores de Tempo , Transativadores/metabolismo , Fatores de Transcrição
13.
FEBS Lett ; 565(1-3): 28-32, 2004 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-15135047

RESUMO

Protein aggregates are oligomeric complexes of misfolded proteins, and serve as the seeds of inclusion bodies termed aggresomes in the cells. Heat shock proteins (Hsps) prevent misfolding and aggregate formation. Here, we found that only avian Hsp25 dominantly accumulated in the aggresomes induced by proteasome inhibition. Molecular cloning of chicken Hsp25 (cHsp25) revealed that it belongs to the Hsp30 family, which is a subfamily of the alpha-crystallin/small Hsp gene family. Unexpectedly, overexpression of cHsp25 into HeLa cells promoted inclusion formation whereas overexpression of mouse Hsp27 and its chicken homologue did not. These results suggest that cHsp25 acts differently from other small Hsps on protein aggregates.


Assuntos
Proteínas de Choque Térmico/fisiologia , Proteínas de Membrana/fisiologia , Proteínas de Neoplasias/fisiologia , Estresse Fisiológico , Sequência de Aminoácidos , Animais , Proteínas Aviárias/biossíntese , Western Blotting , Galinhas , Clonagem Molecular , Cristalinas/química , DNA Complementar/metabolismo , Fibroblastos/metabolismo , Proteínas de Choque Térmico HSP27 , Proteínas de Choque Térmico HSP30 , Células HeLa , Proteínas de Choque Térmico/biossíntese , Proteínas de Choque Térmico/química , Humanos , Corpos de Inclusão , Peptídeos e Proteínas de Sinalização Intracelular , Microscopia de Fluorescência , Chaperonas Moleculares , Dados de Sequência Molecular , Proteínas de Neoplasias/química , Filogenia , Dobramento de Proteína , Proteínas Serina-Treonina Quinases/biossíntese , Codorniz , Homologia de Sequência de Aminoácidos , Ubiquitina/química
14.
FEBS Lett ; 571(1-3): 187-91, 2004 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-15280040

RESUMO

Heat shock proteins (Hsps) are induced in response to various kinds of environmental and physiological stresses. However, it is unclear whether Hsps play roles in protecting cells in the digestive organs against xenobiotic chemicals. Here, we found that feeding induces expression of a set of Hsps specifically in the mouse liver and intestine by activating heat shock transcription factor 1 (HSF1). In the liver, HSF1 is required to suppress toxic effects of electrophiles, which are xenobiotic chemicals causing oxidative stress. We found that overexpression of Hsp27, which elevates cellular glutathione level, promotes survival of culture cells exposed to electrophiles. These results suggest a novel mechanism of cell protection against xenobiotic chemicals in the food.


Assuntos
Ração Animal , Ingestão de Alimentos/fisiologia , Proteínas de Choque Térmico HSP70/genética , Proteínas de Choque Térmico/genética , Estresse Oxidativo/fisiologia , Animais , Proteínas de Ligação a DNA/genética , Glutationa/metabolismo , Células HeLa , Fatores de Transcrição de Choque Térmico , Humanos , Cinética , Fígado/metabolismo , Camundongos , Camundongos Endogâmicos ICR , Especificidade de Órgãos , Fatores de Transcrição
15.
Hear Res ; 182(1-2): 88-96, 2003 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-12948605

RESUMO

To analyze the role of heat shock response in the cochleae, we induced major heat shock proteins, Hsp70, Hsp90, and Hsp27 by perfusion of hot saline into the middle ear cavity (called 'local heat shock') in guinea pigs. Hsps were induced in almost all of the cochlear cells including the sensory hair cells in the organ of Corti. We showed that loss of both the sensory hair cells and the auditory function induced by acoustic overexposure was inhibited by pretreatment of the inner ear with local heat shock. To examine the role of heat shock transcription factor 1(HSF), which activates heat shock genes in response to heat shock, in the protection of sensory hair cells, we analyzed acoustic injury in HSF1-null mice. We found that the loss of sensory hair cells was more significant in HSF1-null mice compared with that of wild-type mice when mice were subjected to acoustic overexposure. These results indicate that HSF1 is required for survival of the sensory hair cells against acoustic overexposure.


Assuntos
Proteínas de Ligação a DNA/fisiologia , Células Ciliadas Auditivas/patologia , Temperatura Alta/efeitos adversos , Ruído/efeitos adversos , Animais , Western Blotting , Morte Celular/fisiologia , Potenciais Evocados Auditivos do Tronco Encefálico , Feminino , Cobaias , Células Ciliadas Auditivas/fisiopatologia , Perda Auditiva Provocada por Ruído/prevenção & controle , Fatores de Transcrição de Choque Térmico , Imuno-Histoquímica , Masculino , Camundongos , Fatores de Transcrição/fisiologia
16.
FEBS Lett ; 587(21): 3541-7, 2013 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-24055475

RESUMO

The febrile response is elicited by pyrogenic cytokines including IL-6 in response to microorganism infections and diseases in vertebrates. Mammalian HSF1, which senses elevations in temperature, negatively regulates the response by suppressing pyrogenic cytokine expression. We here showed that HSF3, an avian ortholog of mammalian HSF1, directly binds to and activates IL-6 during heat shock in chicken cells. Other components of the febrile response mechanism, such as IL-1ß and ATF3, were also differently regulated in mammalian and chicken cells. These results suggest that the febrile response is exacerbated by a feed-forward circuit composed of the HSF3-IL-6 pathway in birds.


Assuntos
Proteínas Aviárias/genética , Galinhas/genética , Resposta ao Choque Térmico/genética , Interleucina-6/genética , Fator 3 Ativador da Transcrição/genética , Fator 3 Ativador da Transcrição/metabolismo , Animais , Proteínas Aviárias/metabolismo , Sequência de Bases , Galinhas/metabolismo , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/metabolismo , Interleucina-6/metabolismo , Dados de Sequência Molecular , Transativadores/genética , Transativadores/metabolismo
17.
Mol Biol Cell ; 22(19): 3571-83, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21813737

RESUMO

Heat shock response is characterized by the induction of heat shock proteins (HSPs), which facilitate protein folding, and non-HSP proteins with diverse functions, including protein degradation, and is regulated by heat shock factors (HSFs). HSF1 is a master regulator of HSP expression during heat shock in mammals, as is HSF3 in avians. HSF2 plays roles in development of the brain and reproductive organs. However, the fundamental roles of HSF2 in vertebrate cells have not been identified. Here we find that vertebrate HSF2 is activated during heat shock in the physiological range. HSF2 deficiency reduces threshold for chicken HSF3 or mouse HSF1 activation, resulting in increased HSP expression during mild heat shock. HSF2-null cells are more sensitive to sustained mild heat shock than wild-type cells, associated with the accumulation of ubiquitylated misfolded proteins. Furthermore, loss of HSF2 function increases the accumulation of aggregated polyglutamine protein and shortens the lifespan of R6/2 Huntington's disease mice, partly through αB-crystallin expression. These results identify HSF2 as a major regulator of proteostasis capacity against febrile-range thermal stress and suggest that HSF2 could be a promising therapeutic target for protein-misfolding diseases.


Assuntos
Encéfalo/crescimento & desenvolvimento , Proteínas de Choque Térmico/genética , Resposta ao Choque Térmico/genética , Peptídeos/metabolismo , Fatores de Transcrição/genética , Animais , Encéfalo/metabolismo , Galinhas , Regulação da Expressão Gênica , Proteínas de Choque Térmico/deficiência , Proteínas de Choque Térmico/metabolismo , Humanos , Proteína Huntingtina , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Peptídeos/química , Dobramento de Proteína , Proteólise , Deficiências na Proteostase/genética , Deficiências na Proteostase/metabolismo , Fatores de Transcrição/deficiência , Fatores de Transcrição/metabolismo , Cadeia B de alfa-Cristalina/genética , Cadeia B de alfa-Cristalina/metabolismo
18.
Mol Biol Cell ; 21(1): 106-16, 2010 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-19864465

RESUMO

The heat-shock response is characterized by the expression of a set of classical heat-shock genes, and is regulated by heat-shock transcription factor 1 (HSF1) in mammals. However, comprehensive analyses of gene expression have revealed very large numbers of inducible genes in cells exposed to heat shock. It is believed that HSF1 is required for the heat-inducible expression of these genes although HSF2 and HSF4 modulate some of the gene expression. Here, we identified a novel mouse HSF3 (mHSF3) translocated into the nucleus during heat shock. However, mHSF3 did not activate classical heat-shock genes such as Hsp70. Remarkably, overexpression of mHSF3 restored the expression of nonclassical heat-shock genes such as PDZK3 and PROM2 in HSF1-null mouse embryonic fibroblasts (MEFs). Although down-regulation of mHSF3 expression had no effect on gene expression or cell survival in wild-type MEF cells, it abolished the moderate expression of PDZK3 mRNA and reduced cell survival in HSF1-null MEF cells during heat shock. We propose that mHSF3 represents a unique HSF that has the potential to activate only nonclassical heat-shock genes to protect cells from detrimental stresses.


Assuntos
Regulação da Expressão Gênica , Proteínas de Choque Térmico/metabolismo , Resposta ao Choque Térmico/genética , Fatores de Transcrição/metabolismo , Animais , Células COS , Núcleo Celular/metabolismo , Galinhas , Chlorocebus aethiops , Citoproteção , DNA/metabolismo , DNA Helicases/metabolismo , Genoma/genética , Proteínas de Choque Térmico HSP70/genética , Proteínas de Choque Térmico HSP70/metabolismo , Humanos , Camundongos , Dados de Sequência Molecular , Família Multigênica/genética , Proteínas Nucleares/metabolismo , Ligação Proteica , Transporte Proteico , Estresse Fisiológico , Temperatura
20.
J Biol Chem ; 283(44): 29961-70, 2008 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-18755693

RESUMO

Heat shock transcription factors (HSFs) regulate gene expression in response to heat shock and in physiological conditions. In mammals, HSF1 is required for heat-mediated induction of classic heat shock genes; however, we do not know the molecular mechanisms by which HSF4 regulates gene expression or the biological consequences of its binding to chromatin. Here, we identified that HSF4 binds to various genomic regions, including the introns and distal parts of protein-coding genes in vivo in mouse lenses, and a substantial numbers of the regions were also occupied by HSF1 and HSF2. HSF4 regulated expression of some genes at a developmental stage when HSF1 and HSF2 expression decreased. Although HSF4 binding did not affect expression of many genes, it induces demethylated status of histone H3K9 on the binding regions. Unexpectedly, a lot of HSF4 targets were induced by heat shock treatment, and HSF4 is required for induction of a set of non-classic heat shock genes in response to heat shock, in part by facilitating HSF1 binding through chromatin modification. These results suggest novel mechanisms of gene regulation controlled by HSF4 in non-classic heat shock response and in lens development.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Cristalino/metabolismo , Fatores de Transcrição/metabolismo , Animais , Sequência de Bases , Cromatina/química , Cromatina/metabolismo , Cromatografia em Gel , Fatores de Transcrição de Choque Térmico , Proteínas de Choque Térmico/metabolismo , Humanos , Cristalino/embriologia , Camundongos , Dados de Sequência Molecular , Ligação Proteica , Fatores de Tempo
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