Kruppel样因子15——多功能转录因子的功能研究
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摘要
Kruppel样因子15(KLF15)是Kruppel样转录因子家族中的一员。Kruppel样转录因子家族特征性结构是含有3个Kruppel样锌指结构,与DNA的CACCC元件和富含GC区连接,从而调控转录激活或抑制。KLF15在许多生物过程中起重要作用,包括细胞的增殖、分化、发展和凋亡。研究证实,KLF15参与调节三大物质代谢:糖代谢、脂肪酸代谢、氨基酸代谢。在循环系统方面,KLF15过表达能够抑制心肌肥厚,而KLF15的缺乏会引起心力衰竭、主动脉瘤的产生。此外,KLF15在肾病、肾纤维化、骨骼肌脂质利用、昼夜节律等诸多方面起重要作用。随着对KLF15功能的认识越来越深入,KLF15有望成为有效治疗致死性疾病的新靶点。
The transcription factor of the Kruppel-like factor-15( LF15) is one of the Kruppel-like factor family. The characteristic feature of this family is the presence of three Kruppel-like zinc fingers,which bind to CACCC elements and GC-rich regions of DNA,to mediate activation and /or repression of transcription.KLF15 plays an important role in many biological processes including: proliferation,differentiation,development and apoptosis. It has been confirmed that KLF15 regulates three metabolisms: sugar metabolism,fatty acid metabolism,amino acid metabolism. In terms of circulation system,KLF15 overexpression can inhibit myocardial hypertrophy,and the lack of KLF15 can lead to heart failure,aortic aneurysm. In addition,KLF15 plays an important role in kidney disease,renal fibrosis,skeletal muscle lipid utilization,circadian rhythm,and many other aspects. Along with the deepening of the understanding of KLF15 function,KLF15 is expected to become a new target for effective treatment of fatal diseases.
The transcription factor of the Kruppel-like factor-15( LF15) is one of the Kruppel-like factor family. The characteristic feature of this family is the presence of three Kruppel-like zinc fingers,which bind to CACCC elements and GC-rich regions of DNA,to mediate activation and /or repression of transcription.KLF15 plays an important role in many biological processes including: proliferation,differentiation,development and apoptosis. It has been confirmed that KLF15 regulates three metabolisms: sugar metabolism,fatty acid metabolism,amino acid metabolism. In terms of circulation system,KLF15 overexpression can inhibit myocardial hypertrophy,and the lack of KLF15 can lead to heart failure,aortic aneurysm. In addition,KLF15 plays an important role in kidney disease,renal fibrosis,skeletal muscle lipid utilization,circadian rhythm,and many other aspects. Along with the deepening of the understanding of KLF15 function,KLF15 is expected to become a new target for effective treatment of fatal diseases.
引文
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[3]Ahmed M,Gaffen SL.IL-17 inhibits adipogenesis in part via C/EBPalpha,PPARgamma and Kruppel-like factors[J].Cytokine,2013,61(3):898-905.
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[6]Fei Z,Bera TK,Liu X,et al.Ankrd26 gene disruption enhances adipogenesis of mouse embryonic fibroblasts[J].J Biol Chem,2011,286(31):27761-27768.
[7]Nagare T,Sakaue H,Matsumoto M,et al.Overexpression of KLF15transcription factor in adipocytes of mice results in down-regulation of SCD1 protein expression in adipocytes and consequent enhancement of glucose-induced insulin secretion[J].J Biol Chem,2011,286(43):37458-37469.
[8]Yamamoto J,Ikeda Y,Iguchi H,et al.A Kruppel-like factor KLF15contributes fasting-induced transcriptional activation of mitochondrial acetyl-CoA synthetase gene AceCS2[J].J Biol Chem,2004,279(17):16954-16962.
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[10]Haldar SM,Lu Y,Jeyaraj D,et al.KLF15 deficiency is a molecular link between heart failure and aortic aneurysm formation[J].Sci Transl Med,2010,2(26):26ra26.
[11]Noack C,Zafiriou MP,Schaeffer H J,et al.Krueppel-like factor 15regulates Wnt/beta-catenin transcription and controls cardiac progenitor cell fate in the postnatal heart[J].EMBO Mol Med,2012,4(9):992-1007.
[12]Wang B,Haldar SM,Lu Y,et al.The Kruppel-like factor KLF15inhibits connective tissue growth factor(CTGF)expression in cardiac fibroblasts[J].J Mol Cell Cardiol,2008,45(2):193-197.
[13]Lu Y,Haldar S,Croce K,et al.Kruppel-like factor 15 regulates smooth muscle response to vascular injury--brief report[J].Arterioscler Thromb Vasc Biol,2010,30(8):1550-1552.
[14]Mallipattu SK,Liu R,Zheng F,et al.Kruppel-like factor 15(KLF15)is a key regulator of podocyte differentiation[J].J Biol Chem,2012,287(23):19122-19135.
[15]Wang Y,Mitch WE.Proteins and renal fibrosis:low-protein diets induce Kruppel-like factor-15,limiting renal fibrosis[J].Kidney Int,2011,79(9):933-934.
[16]Gao X,Huang L,Grosjean F,et al.Low-protein diet supplemented with ketoacids reduces the severity of renal disease in 5/6 nephrectomized rats:a role for KLF15[J].Kidney Int,2011,79(9):987-996.
[17]Haldar SM,Jeyaraj D,Anand P,et al.Kruppel-like factor 15 regulates skeletal muscle lipid flux and exercise adaptation[J].Proc Natl Acad Sci U S A,2012,109(17):6739-6744.
[18]Dmitriev P,Petrov A,Ansseau E,et al.The Kruppel-like factor 15as a molecular link between myogenic factors and a chromosome 4q transcriptional enhancer implicated in facioscapulohumeral dystrophy[J].J Biol Chem,2011,286(52):44620-44631.
[19]Jeyaraj D,Haldar SM,Wan X,et al.Circadian rhythms govern cardiac repolarization and arrhythmogenesis[J].Nature,2012,483(7387):96-99.
[20]Jeyaraj D,Scheer FA,Ripperger J A,et al.KIF15 orchestrates circadian nitrogen homeostasis[J].Cell Metab,2012,15(3):311-323.
[21]Masuno K,Haldar SM,Jeyaraj D,et al.Expression profiling identifies KLF15 as a glucocorticoid target that regulates airway hyperresponsiveness[J].Am J Respir Cell Mol Biol,2011,45(3):642-649.
[2]Leenders JJ,Wijnen WJ,van der Made I,et al.Repression of cardiac hypertrophy by KLF15:underlying mechanisms and therapeutic implications[J].PLoS One,2012,7(5):e36754.
[3]Ahmed M,Gaffen SL.IL-17 inhibits adipogenesis in part via C/EBPalpha,PPARgamma and Kruppel-like factors[J].Cytokine,2013,61(3):898-905.
[4]Takashima M,Ogawa W,Hayashi K,et al.Role of KLF15 in regulation of hepatic gluconeogenesis and metformin action[J].Diabetes,2010,59(7):1608-1615.
[5]Gray S,Feinberg MW,Hull S,et al.The Kruppel-like factor KLF15regulates the insulin-sensitive glucose transporter GLUT4[J].J Biol Chem,2002,277(37):34322-34328.
[6]Fei Z,Bera TK,Liu X,et al.Ankrd26 gene disruption enhances adipogenesis of mouse embryonic fibroblasts[J].J Biol Chem,2011,286(31):27761-27768.
[7]Nagare T,Sakaue H,Matsumoto M,et al.Overexpression of KLF15transcription factor in adipocytes of mice results in down-regulation of SCD1 protein expression in adipocytes and consequent enhancement of glucose-induced insulin secretion[J].J Biol Chem,2011,286(43):37458-37469.
[8]Yamamoto J,Ikeda Y,Iguchi H,et al.A Kruppel-like factor KLF15contributes fasting-induced transcriptional activation of mitochondrial acetyl-CoA synthetase gene AceCS2[J].J Biol Chem,2004,279(17):16954-16962.
[9]Fisch S,Gray S,Heymans S,et al.Kruppel-like factor15 is a regulator of cardiomyocyte hypertrophy[J].Proc Natl Acad Sci U S A,2007,104(17):7074-7079.
[10]Haldar SM,Lu Y,Jeyaraj D,et al.KLF15 deficiency is a molecular link between heart failure and aortic aneurysm formation[J].Sci Transl Med,2010,2(26):26ra26.
[11]Noack C,Zafiriou MP,Schaeffer H J,et al.Krueppel-like factor 15regulates Wnt/beta-catenin transcription and controls cardiac progenitor cell fate in the postnatal heart[J].EMBO Mol Med,2012,4(9):992-1007.
[12]Wang B,Haldar SM,Lu Y,et al.The Kruppel-like factor KLF15inhibits connective tissue growth factor(CTGF)expression in cardiac fibroblasts[J].J Mol Cell Cardiol,2008,45(2):193-197.
[13]Lu Y,Haldar S,Croce K,et al.Kruppel-like factor 15 regulates smooth muscle response to vascular injury--brief report[J].Arterioscler Thromb Vasc Biol,2010,30(8):1550-1552.
[14]Mallipattu SK,Liu R,Zheng F,et al.Kruppel-like factor 15(KLF15)is a key regulator of podocyte differentiation[J].J Biol Chem,2012,287(23):19122-19135.
[15]Wang Y,Mitch WE.Proteins and renal fibrosis:low-protein diets induce Kruppel-like factor-15,limiting renal fibrosis[J].Kidney Int,2011,79(9):933-934.
[16]Gao X,Huang L,Grosjean F,et al.Low-protein diet supplemented with ketoacids reduces the severity of renal disease in 5/6 nephrectomized rats:a role for KLF15[J].Kidney Int,2011,79(9):987-996.
[17]Haldar SM,Jeyaraj D,Anand P,et al.Kruppel-like factor 15 regulates skeletal muscle lipid flux and exercise adaptation[J].Proc Natl Acad Sci U S A,2012,109(17):6739-6744.
[18]Dmitriev P,Petrov A,Ansseau E,et al.The Kruppel-like factor 15as a molecular link between myogenic factors and a chromosome 4q transcriptional enhancer implicated in facioscapulohumeral dystrophy[J].J Biol Chem,2011,286(52):44620-44631.
[19]Jeyaraj D,Haldar SM,Wan X,et al.Circadian rhythms govern cardiac repolarization and arrhythmogenesis[J].Nature,2012,483(7387):96-99.
[20]Jeyaraj D,Scheer FA,Ripperger J A,et al.KIF15 orchestrates circadian nitrogen homeostasis[J].Cell Metab,2012,15(3):311-323.
[21]Masuno K,Haldar SM,Jeyaraj D,et al.Expression profiling identifies KLF15 as a glucocorticoid target that regulates airway hyperresponsiveness[J].Am J Respir Cell Mol Biol,2011,45(3):642-649.