转录因子KLF家族的结构、功能及调控机制研究进展
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摘要
转录因子KLF家族(Krüppel-like factors)成员的C-末端区域中均存在3个保守的Cys2/His2锌指结构,它们能够参与调控真核生物的多种生理过程并发挥重要作用,包括促进脂肪组织和肌肉形成、影响神经系统发育、参与肿瘤发生过程、调控细胞和组织及系统水平的代谢和修复损伤的代谢组织等,是当前生物领域的研究热点。因此,综述了KLF家族成员的共同结构特征,以及KLF3、KLF5、KLF6、KLF7、KLF8、KLF14、KLF15的主要生理功能及其调控机制的研究进展,为未来进一步探讨KLF家族转录因子的作用和相关疾病的分子机制提供参考。
Members of the Krüppel-like factors(KLFs),which are characterized by the presence of three conserved Cys2/His2 zinc-fingers in the C-terminal region,and control varieties of biological processes.Recent studies have shown that KLFs can promote the formation of adipose tissue and muscle,affect the development of the nervous system,participate in the regulation of cancer,and play an important role in the metabolic regulation and repair of metabolic tissue at the level of cells,tissues and systems. At present,it has become a hotspot in biological research.This paper summarizes the common structural characteristics of KLFs,and introduces the research progress of KLF3,KLF5,KLF6,KLF7,KLF8,KLF14,KLF15's main physiological functions and regulatory mechanisms to provide reference and direction for future scientific research.
Members of the Krüppel-like factors(KLFs),which are characterized by the presence of three conserved Cys2/His2 zinc-fingers in the C-terminal region,and control varieties of biological processes.Recent studies have shown that KLFs can promote the formation of adipose tissue and muscle,affect the development of the nervous system,participate in the regulation of cancer,and play an important role in the metabolic regulation and repair of metabolic tissue at the level of cells,tissues and systems. At present,it has become a hotspot in biological research.This paper summarizes the common structural characteristics of KLFs,and introduces the research progress of KLF3,KLF5,KLF6,KLF7,KLF8,KLF14,KLF15's main physiological functions and regulatory mechanisms to provide reference and direction for future scientific research.
引文
[1] CHEN C,ZHOU Y,ZHOU Z,et al.Regulation of KLF5 involves the Sp1 ranscription factor in human epithelial cells[J].Gene,2004,330:133-142.
[2] YANG H W,XIA T,CHEN Z L,et al.Cloning,chromosomal localization and expression patterns of porcine Krüppel-like factors 4,5,7 and the early growth response factor 2[J].Biotechnol Lett,2007,29(1):157-163.
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[7] CROSSLEY M,WHITELAW E,PERKINS A,et al.Isolation and characterization of the cDNA encoding BKLF/TEF-2,a major CACCC-box-binding protein in erythroid cells and selected other cells[J].Mol Cell Bio,1996,16(4):1695-1705.
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[13] LEE M Y,Moon J S,Park S W,et al.KLF5 enhances SREBP-1 action in androgen-dependent induction of fatty acid synthase in prostate cancer cells[J].Biochem J,2009,417(1):313-322.
[14] BUCKINGHAM M,BAJARD L,CHANG T,et al.The formation of skeletal muscle:From somite to limb[J].J Anat,2010,202(1):59-68.
[15] HAYASHI S,MANABE I,SUZUKI Y,et al.Klf5 regulates muscle differentiation by directly targeting muscle-specific genes in cooperation with MyoD in mice[J].Elife,2016,5:e17462.
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[18] MATSUMOTO N,KUBO A,LIU H,et al.Developmental regulation of yolk sac hematopoiesis by Krüppel-like factor 6[J].Blood,2006,107(4):1357-1365.
[19] MATSUMOTO K,YOSHITOMI H,ROSSANT J,et al.Liver organogenesis promoted by endothelial cells prior to vascular function[J].Science,2001,294(5542):559-563.
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[22] LAUB F,ALDABE R,FRIEDRICH V J,et al.Developmental expression of mouse Krüppel-like transcription factor KLF7 suggests a potential role in neurogenesis[J].Dev Biol,2001,233(2):305-318.
[23] CAIAZZO M,COLUCCID A L,VOLPICELLI F,et al.Krüppel-like factor 7 is required for olfactory bulb dopaminergic neuron development[J].Exp Cell Res,2011,317(4):464-473.
[24] BLACKMORE M G,WANG Z,LERCH J K,et al.Krüppel-like factor 7 engineered for transcriptional activation promotes axon regeneration in the adult corticospinal tract[J].PNAS,2012,109(19):7517-7522.
[25] WANG X,SHEN Q W,WANG J,et al.KLF7 regulates satellite cell quiescence in response to extracellular signaling[J].Stem Cells,2016,34(5):1310-1320.
[26] LIU N,WANG Y,ZHOU Y,et al.Krüppel-like factor 8 involved in hypoxia promotes the invasion and metastasis of gastric cancer via epithelial to mesenchymal transition[J].Oncol Rep,2014,32(6):2397-2404.
[27] CHEN G,YANG W,JIN W,et al.Lentivirus-mediated gene silencing of KLF8 reduced the proliferation and invasion of gastric cancer cells[J].Mol Biol Rep,2012,39(10):9809-9815.
[28] LI J,YANG X,SUN H,et al.Up-regulation of Krüppel-like factor 8 promotes tumor invasion and indicates poor prognosis for hepatocellular carcinoma[J].Gastroenterology,2010,139(6):2146-2157.
[29] FU W J,LI J C,WU X Y,et al.Small interference RNA targeting Krüppel-like factor 8 inhibits the renal carcinoma 786-0 cells growth in vitro and in vivo[J].J Cancer Res Clin,2010,136(8):1255-1265.
[30] EATON S A,FUNNELL A P W,SUE N,et al.A network of Krüppel-like factors (Klfs):Klf8 is repressed by Klf3 and activated by Klf1 in vivo[J].J Biol Chem,2008,283(40):26937-26947.
[31] GUO Y,FAN Y,ZHANG J,et al.Perhexiline activates KLF14 and reduces atherosclerosis by modulating ApoA-Ⅰproduction[J].J Clin Invest,2015,125(10):3819-3830.
[32] JUNG D Y,CHALASANI U,PAN N,et al.KLF15 is a molecular link between endoplasmic reticulum stress and insulin resistanc[J].PLoS One,2013,8(10):e77851.
[33] SENGUPTA S,PETERSON T R,LAPLANTE M,et al.mTORC1 controls fasting-induced ketogenesis and its modulation by ageing[J].Nature,2010,468(7327):1100-1104.
[34] HASHIMOTO T,COOK W S,QI C,et al.Defect in peroxisome proliferator-activated receptor alpha-inducible fatty acid oxidation determines the severity of hepatic steatosis in response to fasting[J].J Biol Chem,2000,275(37):28918-28928.
[35] TAKEUCHI Y,YAHAGI N,AITA Y,et al.KLF15 enables rapid switching between lipogenesis and gluconeogenesis during fasting[J].Cell Rep,2016,16(9):2373-2386.
[2] YANG H W,XIA T,CHEN Z L,et al.Cloning,chromosomal localization and expression patterns of porcine Krüppel-like factors 4,5,7 and the early growth response factor 2[J].Biotechnol Lett,2007,29(1):157-163.
[3] PEI J,GRISHIN N V.A new family of predicted Krüppel-like factor genes and pseudogenes in placental mammals[J].PLoS One,2013,8(11):e81109.
[4] PROSDOCIMO D A,SABEH M K,JAIN M K.Krüppel-like factors in muscle health and disease[J].Trends in Cardiovascular Med,2015,25(4):278-287.
[5] KIM C K,HE P,BIALKOWSKA A B,et al.SP and KLF transcription factors in digestive physiology and diseases[J].Gastroenterology,2017,152(8):1845-1875.
[6] FARMER S R.Transcriptional control of adipocyte formation[J].Cell Metab,2006,4(4):263-273.
[7] CROSSLEY M,WHITELAW E,PERKINS A,et al.Isolation and characterization of the cDNA encoding BKLF/TEF-2,a major CACCC-box-binding protein in erythroid cells and selected other cells[J].Mol Cell Bio,1996,16(4):1695-1705.
[8] SUE N,JACK B H A,EATON S A,et al.Targeted disruption of the basic Krüppel-like factor gene (Klf3) reveals a role in adipogenesis[J].Molecular and Cellular Biology,2008,28(12):3967-3978.
[9] GROOTECLAES M,DEVERAUX Q,HILDEBRAND J,et al.C-terminal-binding protein corepresses epithelial and proapoptotic gene expression programs[J].Proceedings of the National Academy of Sciences of the United States of America,2003,100(8):4568-4573.
[10] 王海霞,张志威,贺綦,等.鸡KLF3基因的表达规律及其对脂肪细胞分化的影响研究[J].畜牧兽医学报,2015,46(1):26-31.
[11] SALAZARD B,BELLON L,JEAN S,et al.Low-level arsenite activates the transcription of genes involved in adipose differentiation[J].Cell Biol Toxicol,2004,20(6):375-385.
[12] OISHI Y,MANABE I,TOBE K,et al.Krüppel-like transcription factor KLF5 is a key regulatorof adipocyte differentiation[J].Cell Metab,2005,1(1):27-39.
[13] LEE M Y,Moon J S,Park S W,et al.KLF5 enhances SREBP-1 action in androgen-dependent induction of fatty acid synthase in prostate cancer cells[J].Biochem J,2009,417(1):313-322.
[14] BUCKINGHAM M,BAJARD L,CHANG T,et al.The formation of skeletal muscle:From somite to limb[J].J Anat,2010,202(1):59-68.
[15] HAYASHI S,MANABE I,SUZUKI Y,et al.Klf5 regulates muscle differentiation by directly targeting muscle-specific genes in cooperation with MyoD in mice[J].Elife,2016,5:e17462.
[16] BUCKINGHAM M,RIGBY P W.Gene regulatory networks and transcriptional mechanisms that control myogenesis[J].Dev Cell,2014,28(3):225-238.
[17] PENN B H,BERGSTROM D A,DILWORTH F J,et al.A MyoD-generated feed-forward circuit temporally patterns gene expression during skeletal muscle differentiation[J].Genes Dev,2004,18(19):2348-2353.
[18] MATSUMOTO N,KUBO A,LIU H,et al.Developmental regulation of yolk sac hematopoiesis by Krüppel-like factor 6[J].Blood,2006,107(4):1357-1365.
[19] MATSUMOTO K,YOSHITOMI H,ROSSANT J,et al.Liver organogenesis promoted by endothelial cells prior to vascular function[J].Science,2001,294(5542):559-563.
[20] NIKOLOVA G,LAMMERT E.Interdependent development of blood vessels and organs[J].Cell Tissue Res,2003,314(1):33-42.
[21] ZHAO X,MONSON C,GAO C,et al.Klf6/copeb is required for hepatic outgrowth in zebrafish and for hepatocyte specification in mouse ES cells[J].Dev Biol,2010,344(1):79-93.
[22] LAUB F,ALDABE R,FRIEDRICH V J,et al.Developmental expression of mouse Krüppel-like transcription factor KLF7 suggests a potential role in neurogenesis[J].Dev Biol,2001,233(2):305-318.
[23] CAIAZZO M,COLUCCID A L,VOLPICELLI F,et al.Krüppel-like factor 7 is required for olfactory bulb dopaminergic neuron development[J].Exp Cell Res,2011,317(4):464-473.
[24] BLACKMORE M G,WANG Z,LERCH J K,et al.Krüppel-like factor 7 engineered for transcriptional activation promotes axon regeneration in the adult corticospinal tract[J].PNAS,2012,109(19):7517-7522.
[25] WANG X,SHEN Q W,WANG J,et al.KLF7 regulates satellite cell quiescence in response to extracellular signaling[J].Stem Cells,2016,34(5):1310-1320.
[26] LIU N,WANG Y,ZHOU Y,et al.Krüppel-like factor 8 involved in hypoxia promotes the invasion and metastasis of gastric cancer via epithelial to mesenchymal transition[J].Oncol Rep,2014,32(6):2397-2404.
[27] CHEN G,YANG W,JIN W,et al.Lentivirus-mediated gene silencing of KLF8 reduced the proliferation and invasion of gastric cancer cells[J].Mol Biol Rep,2012,39(10):9809-9815.
[28] LI J,YANG X,SUN H,et al.Up-regulation of Krüppel-like factor 8 promotes tumor invasion and indicates poor prognosis for hepatocellular carcinoma[J].Gastroenterology,2010,139(6):2146-2157.
[29] FU W J,LI J C,WU X Y,et al.Small interference RNA targeting Krüppel-like factor 8 inhibits the renal carcinoma 786-0 cells growth in vitro and in vivo[J].J Cancer Res Clin,2010,136(8):1255-1265.
[30] EATON S A,FUNNELL A P W,SUE N,et al.A network of Krüppel-like factors (Klfs):Klf8 is repressed by Klf3 and activated by Klf1 in vivo[J].J Biol Chem,2008,283(40):26937-26947.
[31] GUO Y,FAN Y,ZHANG J,et al.Perhexiline activates KLF14 and reduces atherosclerosis by modulating ApoA-Ⅰproduction[J].J Clin Invest,2015,125(10):3819-3830.
[32] JUNG D Y,CHALASANI U,PAN N,et al.KLF15 is a molecular link between endoplasmic reticulum stress and insulin resistanc[J].PLoS One,2013,8(10):e77851.
[33] SENGUPTA S,PETERSON T R,LAPLANTE M,et al.mTORC1 controls fasting-induced ketogenesis and its modulation by ageing[J].Nature,2010,468(7327):1100-1104.
[34] HASHIMOTO T,COOK W S,QI C,et al.Defect in peroxisome proliferator-activated receptor alpha-inducible fatty acid oxidation determines the severity of hepatic steatosis in response to fasting[J].J Biol Chem,2000,275(37):28918-28928.
[35] TAKEUCHI Y,YAHAGI N,AITA Y,et al.KLF15 enables rapid switching between lipogenesis and gluconeogenesis during fasting[J].Cell Rep,2016,16(9):2373-2386.