CHIP促进心肌素泛素化和降解及抑制平滑肌细胞分化的分子机理
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摘要
正常血管平滑肌细胞(SMC)高度分化,但是在血管损伤效应发生时,SMC则向增殖表型转换。研究表明许多因素包括生长因子、细胞因子、转录因子等可调节血管SMC表型转化。其中心肌素(myocardin)是近年来在平滑肌细胞分化和表型转换方面具有重要意义的一个发现。目前已知,心肌素是最有效的SRF(serumresponse factor)共同激活因子,通过Q-富集功能区与SRF结合形成复合物,激活CArG盒子依赖的平滑肌细胞标志基因的表达,是平滑肌细胞发育和分化所必需的共激活转录因子。但是到目前为止,调节心肌素蛋白水平和活性的分子机制尚未完全阐明。
近年来,人们发现转录后修饰特别是磷酸化、Sumoylation和泛素化对底物蛋白和酶的活性具有重要的调节作用。其中,泛素E3连接酶可有效地识别和泛素化蛋白底物,促进其被泛素-蛋白酶体系统(ubiquitin-proteasome system)降解。CHIP(Hsc70羧基末端反应蛋白)是一个重要的控制蛋白质量的泛素E3连接酶,可促进多种蛋白底物被泛素-蛋白酶体系统降解和清除,在心肌细胞损伤、细胞凋亡、肿瘤、热应急等方面起着非常重要的作用。但是CHIP调节SMC表型转换和动脉血管收缩性的分子机制尚未见报道。
因此,本研究主要探讨了CHIP调节心肌素的蛋白水平和活性,促进SMC表型转化的分子机制。我们发现:
1)过度表达CHIP不仅抑制心肌素依赖的SMC标志基因如SMα-actin,SM-MHC和SM22α的表达,显著降低SM22α-luc或ANF-luc荧光素酶报告基因活性和心肌素的蛋白水平,而且这种抑制效应依赖于CHIP U-box结构域的存在。
2)转染siRNA-CHIP不仅促进SMC标志基因的表达,而且使SM22α报告基因活性明显增加。
3) GST-pull down和免疫共沉淀实验证实CHIP在体内外均可与心肌素直接相互结合,而不是通过Hsp70和Hsp90。CHIP正负电荷区是结合心肌素的结构域,而心肌素C末端的TAD转录激活区是结合CHIP的结构域。免疫组化染色显示它们共定位于SMC胞浆中。
4) Pulse-chase实验结果表明CHIP能明显下调心肌素的蛋白水平,而且这种作用可以被蛋白酶体抑制剂MG132阻断。体内外泛素化实验进一步证明CHIP可以促进心肌素泛素化和降解,而且这种泛素化过程依赖于CHIP E3连接酶活性。同时,心肌素的TAD结构域是被CHIP泛素化所必需的。
5) CHIP介导的心肌素泛素化依赖GSK-3β诱导的磷酸化修饰。
6)在动脉环中过度表达CHIP可明显降低血管心肌素蛋白水平及其所依赖的SMC标志基因的表达,而且动脉环收缩性明显降低,舒张性明显增加。
本研究结果表明CHIP可通过泛素—蛋白酶体系统降低心肌素的蛋白水平和转录活性,抑制SMC表型转换和血管收缩性。这一机制的阐明可能为动脉粥样硬化、高血压和老年痴呆症等重大疾病的防治提供了重要的新思路。
The phenotypic modulation of vascular muscle cells(SMCs) from differentiation to dedifferentiation is a critical feature of the onset and progression of the vascular remodeling under vessels injury conditions.There has been much progress in recent years to identify mechanisms including growth factors,cytokines and transcription factors that control expression of the repertoire of genes that are specific or selective for the vascular SMC and required for its differentiated function.One of the most exciting recent discoveries was the identification of the serum response factor(SRF) coactivator myocardin that appears to be required for expression of many SMC differentiation marker genes and for initial differentiation of SMC during development.During the process of SMC development and differentiation,myocardin plays a pivotal role in activating CArG-dependent genes expression through its combination with SRF with its Q-rich domain.However,it remains unclear about the molecular mechanism by which the protein level and activity of myocardin can be modulated.
It is an important role for post-transcription modifications in modulating protein level and activity,especially as phosphorylation,sumoylation and ubiquitination.As referred to ubiquitination,E3 ligase can effectively and specifically recognize and ubiquitinate substrates,enhancing them degradation through proteasome.CHIP,known as an E3 ligase,can degradate multiple protein substrates through proteasome,playing an important role in pathological progress and ailments conditions like cardiomyocyte injury, apoptosis,neoplasm and thermo-stress.However,there is no report about the molecular mechanism by which CHIP can modulate SMC phenotype transformation and aortic contractility.
Therefore,we focus on the molecular mechanism about CHIP modulating myocardin protein level and its activity as well as SMC phenotype modulation and we found that:
1) CHIP overexpression not only inhibits myocardin-dependent SMC marker genes expression such as SMα-actin,SM-MHC and SM22α,but also dramatically decreases the SM22α-luc and ANF-luc luciferase report activity in U-box domain dependent manner.
2) Knockout of CHIP by siRNA can promote SMC contractile marker genes and increase the SM22αluciferase reporter activity.
3) GST-pull down and Co-ip assay demonstrate the direct interaction between CHIP and myocardin in vivo and in vitro and this interaction is not dependent on the existence of hsp70 or hsp90.CHIP charged domain and myocardin TAD domain are responsible for their interaction.Immunostaining indicates that CHIP is colocalized with myocardin in SMC.
4) Pulse-chase assay indicates that CHIP rapidly decreases the level of myocardin protein,whereas proteasome inhibitor MG132 can attenuate this effect.The ubiquitination reactions in vivo and in vitro reveal that myocardin ubiquitination is dependent on E3 ligase activity of CHIP,and the myocardin TAD domain is required for its interaction with CHIP and its ubiquitination.
5) CHIP specifically promotes phosphorylated myocardin ubiquitination-degradation in vivo and in vitro.
6) In ex vivo aortic ring,CHIP overexpression downregulates the myocardin protein level and its dependent contractile gene transcription.Moreover,Rat aortic rings transduced with Ad-CHIP show significantly reduced contraction and increased relaxation.
In conclusion,CHIP plays a critical role in modulating myocardin protein level and transactivity,and controlling the SMC phenotype and arterial tone through ubiquitin-proteosome system.This proposed mechanism may be associated with atherosclerosis,hypertension,and Alzheimer's disease,opening a new therapeutic approach to these diseases' prevention and treatment.
近年来,人们发现转录后修饰特别是磷酸化、Sumoylation和泛素化对底物蛋白和酶的活性具有重要的调节作用。其中,泛素E3连接酶可有效地识别和泛素化蛋白底物,促进其被泛素-蛋白酶体系统(ubiquitin-proteasome system)降解。CHIP(Hsc70羧基末端反应蛋白)是一个重要的控制蛋白质量的泛素E3连接酶,可促进多种蛋白底物被泛素-蛋白酶体系统降解和清除,在心肌细胞损伤、细胞凋亡、肿瘤、热应急等方面起着非常重要的作用。但是CHIP调节SMC表型转换和动脉血管收缩性的分子机制尚未见报道。
因此,本研究主要探讨了CHIP调节心肌素的蛋白水平和活性,促进SMC表型转化的分子机制。我们发现:
1)过度表达CHIP不仅抑制心肌素依赖的SMC标志基因如SMα-actin,SM-MHC和SM22α的表达,显著降低SM22α-luc或ANF-luc荧光素酶报告基因活性和心肌素的蛋白水平,而且这种抑制效应依赖于CHIP U-box结构域的存在。
2)转染siRNA-CHIP不仅促进SMC标志基因的表达,而且使SM22α报告基因活性明显增加。
3) GST-pull down和免疫共沉淀实验证实CHIP在体内外均可与心肌素直接相互结合,而不是通过Hsp70和Hsp90。CHIP正负电荷区是结合心肌素的结构域,而心肌素C末端的TAD转录激活区是结合CHIP的结构域。免疫组化染色显示它们共定位于SMC胞浆中。
4) Pulse-chase实验结果表明CHIP能明显下调心肌素的蛋白水平,而且这种作用可以被蛋白酶体抑制剂MG132阻断。体内外泛素化实验进一步证明CHIP可以促进心肌素泛素化和降解,而且这种泛素化过程依赖于CHIP E3连接酶活性。同时,心肌素的TAD结构域是被CHIP泛素化所必需的。
5) CHIP介导的心肌素泛素化依赖GSK-3β诱导的磷酸化修饰。
6)在动脉环中过度表达CHIP可明显降低血管心肌素蛋白水平及其所依赖的SMC标志基因的表达,而且动脉环收缩性明显降低,舒张性明显增加。
本研究结果表明CHIP可通过泛素—蛋白酶体系统降低心肌素的蛋白水平和转录活性,抑制SMC表型转换和血管收缩性。这一机制的阐明可能为动脉粥样硬化、高血压和老年痴呆症等重大疾病的防治提供了重要的新思路。
The phenotypic modulation of vascular muscle cells(SMCs) from differentiation to dedifferentiation is a critical feature of the onset and progression of the vascular remodeling under vessels injury conditions.There has been much progress in recent years to identify mechanisms including growth factors,cytokines and transcription factors that control expression of the repertoire of genes that are specific or selective for the vascular SMC and required for its differentiated function.One of the most exciting recent discoveries was the identification of the serum response factor(SRF) coactivator myocardin that appears to be required for expression of many SMC differentiation marker genes and for initial differentiation of SMC during development.During the process of SMC development and differentiation,myocardin plays a pivotal role in activating CArG-dependent genes expression through its combination with SRF with its Q-rich domain.However,it remains unclear about the molecular mechanism by which the protein level and activity of myocardin can be modulated.
It is an important role for post-transcription modifications in modulating protein level and activity,especially as phosphorylation,sumoylation and ubiquitination.As referred to ubiquitination,E3 ligase can effectively and specifically recognize and ubiquitinate substrates,enhancing them degradation through proteasome.CHIP,known as an E3 ligase,can degradate multiple protein substrates through proteasome,playing an important role in pathological progress and ailments conditions like cardiomyocyte injury, apoptosis,neoplasm and thermo-stress.However,there is no report about the molecular mechanism by which CHIP can modulate SMC phenotype transformation and aortic contractility.
Therefore,we focus on the molecular mechanism about CHIP modulating myocardin protein level and its activity as well as SMC phenotype modulation and we found that:
1) CHIP overexpression not only inhibits myocardin-dependent SMC marker genes expression such as SMα-actin,SM-MHC and SM22α,but also dramatically decreases the SM22α-luc and ANF-luc luciferase report activity in U-box domain dependent manner.
2) Knockout of CHIP by siRNA can promote SMC contractile marker genes and increase the SM22αluciferase reporter activity.
3) GST-pull down and Co-ip assay demonstrate the direct interaction between CHIP and myocardin in vivo and in vitro and this interaction is not dependent on the existence of hsp70 or hsp90.CHIP charged domain and myocardin TAD domain are responsible for their interaction.Immunostaining indicates that CHIP is colocalized with myocardin in SMC.
4) Pulse-chase assay indicates that CHIP rapidly decreases the level of myocardin protein,whereas proteasome inhibitor MG132 can attenuate this effect.The ubiquitination reactions in vivo and in vitro reveal that myocardin ubiquitination is dependent on E3 ligase activity of CHIP,and the myocardin TAD domain is required for its interaction with CHIP and its ubiquitination.
5) CHIP specifically promotes phosphorylated myocardin ubiquitination-degradation in vivo and in vitro.
6) In ex vivo aortic ring,CHIP overexpression downregulates the myocardin protein level and its dependent contractile gene transcription.Moreover,Rat aortic rings transduced with Ad-CHIP show significantly reduced contraction and increased relaxation.
In conclusion,CHIP plays a critical role in modulating myocardin protein level and transactivity,and controlling the SMC phenotype and arterial tone through ubiquitin-proteosome system.This proposed mechanism may be associated with atherosclerosis,hypertension,and Alzheimer's disease,opening a new therapeutic approach to these diseases' prevention and treatment.
引文
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[1]Wang D,Chang PS,Wang Z,Sutherland L,Richardson JA,Small E,et al.Activation of cardiac gene expression by myocardin,a transcriptional cofactor for serum response factor.Cell 2001;105(7):851-862.
[2]Li S,Wang DZ,Wang Z,Richardson JA,Olson EN.The serum response factor coactivator myocardin is required for vascular smooth muscle development.Proceedings of the National Academy of Sciences of the United States of America 2003;100(16):9366-9370.
[3]Kawai-Kowase K,Owens GK.Multiple repressor pathways contribute to phenotypic switching of vascular smooth muscle cells.Am J Physiol Cell Physiol 2007;292(1):C59-69.
[4]Owens GK,Kumar MS,Wamhoff BR.Molecular regulation of vascular smooth muscle cell differentiation in development and disease.Physiol Rev 2004;84(3):767-801.
[5]Creemers EE,Sutherland LB,Oh J,Barbosa AC,Olson EN.Coactivation of MEF2 by the SAP domain proteins myocardin and MASTR.Molecular cell 2006;23(1):83-96.
[6]Du KL,Ip HS,Li J,Chen M,Dandre F,Yu W,et al.Myocardin is a critical serum response factor cofactor in the transcriptional program regulating smooth muscle cell differentiation.Molecular and cellular biology 2003;23(7):2425-2437.
[7]Wang DZ,Li S,Hockemeyer D,Sutherland L,Wang Z,Schratt G,et al.Potentiation of serum response factor activity by a family of myocardin-related transcription factors.Proceedings of the National Academy of Sciences of the United States of America 2002;99(23):14855-14860.
[8]Aravind L,Koonin EV.SAP-a putative DNA-binding motif involved in chromosomal organization.Trends in biochemical sciences 2000;25(3):112-114.
[9]Wang Z,Wang DZ,Pipes GC,Olson EN.Myocardin is a master regulator of smooth muscle gene expression.Proceedings of the National Academy of Sciences of the United States of America 2003;100(12):7129-7134.
[10]Chen J,Kitchen CM,Streb JW,Miano JM.Myocardin:a component of a molecular switch for smooth muscle differentiation.Journal of molecular and cellular cardiology 2002;34(10):1345-1356.
[11]Creemers EE,Sutherland LB,McAnally J,Richardson JA,Olson EN.Myocardin is a direct transcriptional target of Mef2,Tead and Foxo proteins during cardiovascular development.Development (Cambridge,England)2006;133(21):4245-4256.
[12]Liu ZP,Wang Z,Yanagisawa H,Olson EN.Phenotypic modulation of smooth muscle cells through interaction of Foxo4 and myocardin.Developmental cell 2005;9(2):261-270.
[13]Callis TE,Cao D,Wang DZ.Bone morphogenetic protein signaling modulates myocardin transactivation of cardiac genes.Circ Res 2005;97(10):992-1000.
[14]Qiu P,Ritchie RP,Fu Z,Cao D,Cumming J,Miano JM,et al.Myocardin enhances Smad3-mediated transforming growth factor-betal signaling in a CArG box-independent manner:Smad-binding element is an important cis element for SM22alpha transcription in vivo.Circulation research 2005;97(10):983-991.
[15]Molkentin JD,Dorn IG,2nd.Cytoplasmic signaling pathways that regulate cardiac hypertrophy.Annual review of physiology 2001;63:391-426.
[16]Cao D,Wang Z,Zhang CL,Oh J,Xing W,Li S,et al.Modulation of smooth muscle gene expression by association of histone acetyltransferases and deacetylases with myocardin.Molecular and cellular biology 2005;25(1):364-376.
[17]Qiu P,Ritchie RP,Gong XQ.Hamamori Y,Li L.Dynamic changes in chromatin acetylation and the expression of histone acetyltransferases and histone deacetylases regulate the SM22alpha transcription in response to Smad3-mediated TGFbetal signaling.Biochemical and biophysical research communications 2006;348(2):351-358.
[18]Huang J,Cheng L,Li J,Chen M,Zhou D,Lu MM,et al.Myocardin regulates expression of contractile genes in smooth muscle cells and is required for closure of the ductus arteriosus in mice.The Journal of clinical investigation 2008;118(2):515-525.
[19]Small EM,Warkman AS,Wang DZ,Sutherland LB,Olson EN,Krieg PA.Myocardin is sufficient and necessary for cardiac gene expression in Xenopus.Development (Cambridge,England)2005;132(5):987-997.
[20]Xing W,Zhang TC,Cao D,Wang Z,Antos CL,Li S,et al.Myocardin induces cardiomyocyte hypertrophy.Circulation research 2006;98(8):1089-1097.
[21]Rosser MF,Washburn E,Muchowski PJ,Patterson C,Cyr DM.Chaperone functions of the E3 ubiquitin ligase CHIP.J Biol Chem 2007;282(31):22267-22277.
[22]Wang J,Feng XH,Schwartz RJ.SUMO-1 modification activated GATA4-dependent cardiogenic gene activity.The Journal of biological chemistry 2004;279(47):49091-49098.
[23]Wang J,Li A,Wang Z,Feng X,Olson EN,Schwartz RJ.Myocardin sumoylation transactivates cardiogenic genes in pluripotent 10T1/2 fibroblasts.Molecular and cellular biology 2007;27(2):622-632.
[24]Antos CL,McKinsey TA,Frey N,Kutschke W,McAnally J,Shelton JM,et al.Activated glycogen synthase-3 beta suppresses cardiac hypertrophy in vivo.Proceedings of the National Academy of Sciences of the United States of America 2002;99(2):907-912.
[25]Haq S,Choukroun G,Kang ZB,Ranu H,Matsui T,Rosenzweig A,et al.Glycogen synthase kinase-3beta is a negative regulator of cardiomyocyte hypertrophy.The Journal of cell biology 2000;151(1):117-130.
[26]Badorff C,Seeger FH,Zeiher AM,Dimmeler S.Glycogen synthase kinase 3beta inhibits myocardin-dependent transcription and hypertrophy induction through site-specific phosphorylation.Circulation research 2005;97(7):645-654.
[27]Ueyama T,Kasahara H,Ishiwata T,Nie Q,Izumo S.Myocardin expression is regulated by Nkx2.5,and its function is required for cardiomyogenesis.Molecular and cellular biology 2003;23(24):9222-9232.
[28]Yoshida T,Sinha S,Dandre F,Wamhoff BR,Hoofnagle MH,Kremer BE,et al.Myocardin is a key regulator of CArG-dependent transcription of multiple smooth muscle marker genes.Circulation research 2003;92(8):856-864.
[29]Wang Z,Wang DZ,Hockemeyer D,McAnally J,Nordheim A,Olson EN.Myocardin and ternary complex factors compete for SRF to control smooth muscle gene expression.Nature 2004;428(6979):185-189.
[30]Yoshida T,Gan Q,Shang Y,Owens GK.Platelet-derived growth factor-BB represses smooth muscle cell marker genes via changes in binding of MKL factors and histone deacetylases to their promoters.American journal of physiology 2007;292(2):C886-895.
[31]Zhou J,Hu G,Herring BP.Smooth muscle-specific genes are differentially sensitive to inhibition by Elk-1.Molecular and cellular biology 2005;25(22):9874-9885.
[32]Wamhoff BR,Hoofnagle MH,Burns A,Sinha S,McDonald OG,Owens GK.AG/C element mediates repression of the SM22alpha promoter within phenotypically modulated smooth muscle cells in experimental atherosclerosis.Circulation research 2004;95(10):981-988.
[33]McDonald OG,Wamhoff BR,Hoofnagle MH,Owens GK.Control of SRF binding to CArG box chromatin regulates smooth muscle gene expression in vivo.The Journal of clinical investigation 2006;116(1):36-48.
[34]Mack CP,Somlyo AV,Hautmann M,Somlyo AP,Owens GK.Smooth muscle differentiation marker gene expression is regulated by RhoA-mediated actin polymerization.The Journal of biological chemistry 2001;276(1):341-347.
[35]Liu HW,Halayko AJ,Fernandes DJ,Harmon GS,McCauley JA,Kocieniewski P,et al.The RhoA/Rho kinase pathway regulates nuclear localization of serum response factor.American journal of respiratory cell and molecular biology 2003;29(1):39-47.
[36]Li HJ,Haque Z,Lu Q,Li L,Karas R,Mendelsohn M.Steroid receptor coactivator 3 is a coactivator for myocardin,the regulator of smooth muscle transcription and differentiation.Proceedings of the National Academy of Sciences of the United States of America 2007;104(10):4065-4070.
[37]Hayashi K,Nakamura S,Nishida W,Sobue K.Bone morphogenetic protein-induced MSX1 and MSX2 inhibit myocardin-dependent smooth muscle gene transcription.Mol Cell Biol 2006;26(24):9456-9470.
[38]Proweller A,Pear WS,Parmacek MS.Notch signaling represses myocardin-induced smooth muscle cell differentiation.The Journal of biological chemistry 2005;280(10):8994-9004.
[39]Doi H,Iso T,Yamazaki M,Akiyama H,Kanai H,Sato H,et al.HERP1 inhibits myocardin-induced vascular smooth muscle cell differentiation by interfering with SRF binding to CArG box.Arteriosclerosis,thrombosis,and vascular biology 2005;25(11):2328-2334.
[40]Liu Y,Sinha S,McDonald OG,Shang Y,Hoofnagle MH,Owens GK.Kruppel-like factor 4 abrogates myocardin-induced activation of smooth muscle gene expression.The Journal of biological chemistry 2005;280(10):9719-9727.
[41]Liu Y,Sinha S,Owens G A transforming growth factor-beta control element required for SM alpha-actin expression in vivo also partially mediates GKLF-dependent transcriptional repression.J Biol Chem 2003;278(48):48004-48011.
[42]Adam P.T,Regan CP,Hautmann MB,Owens GK.Positive-and negative-acting Kruppel-like transcription factors bind a transforming growth factor beta control element required for expression of the smooth muscle cell differentiation marker SM22alpha in vivo.J Biol Chem 2000;275(48):37798-37806.
[2]Olson ES,Dong W.Nonlinearity in intracochlear pressure.ORL J Otorhinolaryngol Relat Spec 2006;68(6):359-364.
[3]Li S,Wang DZ,Wang Z,Richardson JA,Olson EN.The serum response factor coactivator myocardin is required for vascular smooth muscle development.Proceedings of the National Academy of Sciences of the United States of America 2003;100(16):9366-9370.
[4]Kawai-Kowase K,Owens GK.Multiple repressor pathways contribute to phenotypic switching of vascular smooth muscle cells.Am J Physiol Cell Physiol 2007;292(1):C59-69.
[5]Wang DZ,Olson EN.Control of smooth muscle development by the myocardin family of transcriptional coactivators.Curr Opin Genet Dev 2004;14(5):558-566.
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[7]Huang J,Cheng L,Li J,Chen M,Zhou D,Lu MM,et al.Myocardin regulates expression of contractile genes in smooth muscle cells and is required for closure of the ductus arteriosus in mice.The Journal of clinical investigation 2008;118(2):515-525.
[8]Yoshida T,Gan Q,Shang Y,Owens GK.Platelet-derived growth factor-BB represses smooth muscle cell marker genes via changes in binding of MKL factors and histone deacetylases to their promoters.American journal of physiology 2007;292(2):C886-895.
[9]Wang Z,Wang DZ,Hockemeyer D,McAnally J,Nordheim A,Olson EN.Myocardin and ternary complex factors compete for SRF to control smooth muscle gene expression.Nature 2004;428(6979):185-189.
[10]Zhou J,Hu G,Herring BP.Smooth muscle-specific genes are differentially sensitive to inhibition by Elk-1.Molecular and cellular biology 2005;25(22):9874-9885.
[11]Wamhoff BR,Hoofnagle MH,Burns A,Sinha S,McDonald OG,Owens GK.A G/C element mediates repression of the SM22alpha promoter within phenotypically modulated smooth muscle cells in experimental atherosclerosis.Circulation research 2004;95(10):981-988.
[12]McDonald OG,Wamhoff BR,Hoofnagle MH,Owens GK.Control of SRF binding to CArG box chromatin regulates smooth muscle gene expression in vivo.The Journal of clinical investigation 2006;116(1):36-48.
[13]Cao D,Wang Z,Zhang CL,Oh J,Xing W,Li S,et al.Modulation of smooth muscle gene expression by association of histone acetyltransferases and deacetylases with myocardin.Molecular and cellular biology 2005;25(1):364-376.
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[16]Mack CP,Somlyo AV,Hautmann M,Somlyo AP,Owens GK.Smooth muscle differentiation marker gene expression is regulated by RhoA-mediated actin polymerization.The Journal of biological chemistry 2001;276(1):341-347.
[17]Liu HW,Halayko AJ,Fernandes DJ,Harmon GS,McCauley JA,Kocieniewski P,et al.The RhoA/Rho kinase pathway regulates nuclear localization of serum response factor.American journal of respiratory cell and molecular biology 2003;29(1):39-47.
[18]Hayashi K,Nakamura S,Nishida W,Sobue K.Bone morphogenetic protein-induced MSX1 and MSX2 inhibit myocardin-dependent smooth muscle gene transcription.Molecular and cellular biology 2006;26(24):9456-9470.
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[23]Haq S,Choukroun G,Kang ZB,Rami H,Matsui T,Rosenzweig A et al.Glycogen synthase kinase-3beta is a negative regulator of cardiomyocyte hypertrophy.The Journal of cell biology 2000;151(1):117-130.
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[40]Adam PJ,Regan CP,Hautmann MB,Owens GK.Positive-and negative-acting Kruppel-like transcription factors bind a transforming growth factor beta control element required for expression of the smooth muscle cell differentiation marker SM22alpha in vivo.J Biol Chem 2000;275(48):37798-37806.
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[1]Wang D,Chang PS,Wang Z,Sutherland L,Richardson JA,Small E,et al.Activation of cardiac gene expression by myocardin,a transcriptional cofactor for serum response factor.Cell 2001;105(7):851-862.
[2]Li S,Wang DZ,Wang Z,Richardson JA,Olson EN.The serum response factor coactivator myocardin is required for vascular smooth muscle development.Proceedings of the National Academy of Sciences of the United States of America 2003;100(16):9366-9370.
[3]Kawai-Kowase K,Owens GK.Multiple repressor pathways contribute to phenotypic switching of vascular smooth muscle cells.Am J Physiol Cell Physiol 2007;292(1):C59-69.
[4]Owens GK,Kumar MS,Wamhoff BR.Molecular regulation of vascular smooth muscle cell differentiation in development and disease.Physiol Rev 2004;84(3):767-801.
[5]Creemers EE,Sutherland LB,Oh J,Barbosa AC,Olson EN.Coactivation of MEF2 by the SAP domain proteins myocardin and MASTR.Molecular cell 2006;23(1):83-96.
[6]Du KL,Ip HS,Li J,Chen M,Dandre F,Yu W,et al.Myocardin is a critical serum response factor cofactor in the transcriptional program regulating smooth muscle cell differentiation.Molecular and cellular biology 2003;23(7):2425-2437.
[7]Wang DZ,Li S,Hockemeyer D,Sutherland L,Wang Z,Schratt G,et al.Potentiation of serum response factor activity by a family of myocardin-related transcription factors.Proceedings of the National Academy of Sciences of the United States of America 2002;99(23):14855-14860.
[8]Aravind L,Koonin EV.SAP-a putative DNA-binding motif involved in chromosomal organization.Trends in biochemical sciences 2000;25(3):112-114.
[9]Wang Z,Wang DZ,Pipes GC,Olson EN.Myocardin is a master regulator of smooth muscle gene expression.Proceedings of the National Academy of Sciences of the United States of America 2003;100(12):7129-7134.
[10]Chen J,Kitchen CM,Streb JW,Miano JM.Myocardin:a component of a molecular switch for smooth muscle differentiation.Journal of molecular and cellular cardiology 2002;34(10):1345-1356.
[11]Creemers EE,Sutherland LB,McAnally J,Richardson JA,Olson EN.Myocardin is a direct transcriptional target of Mef2,Tead and Foxo proteins during cardiovascular development.Development (Cambridge,England)2006;133(21):4245-4256.
[12]Liu ZP,Wang Z,Yanagisawa H,Olson EN.Phenotypic modulation of smooth muscle cells through interaction of Foxo4 and myocardin.Developmental cell 2005;9(2):261-270.
[13]Callis TE,Cao D,Wang DZ.Bone morphogenetic protein signaling modulates myocardin transactivation of cardiac genes.Circ Res 2005;97(10):992-1000.
[14]Qiu P,Ritchie RP,Fu Z,Cao D,Cumming J,Miano JM,et al.Myocardin enhances Smad3-mediated transforming growth factor-betal signaling in a CArG box-independent manner:Smad-binding element is an important cis element for SM22alpha transcription in vivo.Circulation research 2005;97(10):983-991.
[15]Molkentin JD,Dorn IG,2nd.Cytoplasmic signaling pathways that regulate cardiac hypertrophy.Annual review of physiology 2001;63:391-426.
[16]Cao D,Wang Z,Zhang CL,Oh J,Xing W,Li S,et al.Modulation of smooth muscle gene expression by association of histone acetyltransferases and deacetylases with myocardin.Molecular and cellular biology 2005;25(1):364-376.
[17]Qiu P,Ritchie RP,Gong XQ.Hamamori Y,Li L.Dynamic changes in chromatin acetylation and the expression of histone acetyltransferases and histone deacetylases regulate the SM22alpha transcription in response to Smad3-mediated TGFbetal signaling.Biochemical and biophysical research communications 2006;348(2):351-358.
[18]Huang J,Cheng L,Li J,Chen M,Zhou D,Lu MM,et al.Myocardin regulates expression of contractile genes in smooth muscle cells and is required for closure of the ductus arteriosus in mice.The Journal of clinical investigation 2008;118(2):515-525.
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