MELK的功能及其在肿瘤研究中的进展
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摘要
母体胚胎亮氨酸拉链激酶(MELK)是蔗糖非发酵1/AMP活化蛋白激酶(Snf1/AMPK)家族中一个独特成员,是一种周期依赖性激酶。与家族其他成员不同,MELK并不参与代谢应激状态下细胞的生存调控,而更多参与细胞周期、细胞增殖、肿瘤生成和细胞凋亡等过程。MELK在人体多种肿瘤中表达升高,与肿瘤的预后密切相关。MELK在肿瘤干细胞中被异常激活,使肿瘤细胞获得生长、侵袭、迁移等能力,因此,MELK可以作为肿瘤治疗的重要靶点。我们就MELK基因的生物学功能、作用机制及其在肿瘤研究中的进展做简要综述。
Maternal embryonic leucine zipper kinase(MELK) is a cell cycle-dependent protein kinase, which be-longs to the Snf1/AMPK family of serine-threonine kinases.Unlike most members of this family only functioningin cell survival under metabolically environmental stress, MELK participates in diverse processes, including cell cy-cle, cell proliferation, apoptosis, RNA processing, and embryonic development. The overexpression of MELK in vari-ous cancers results in poor patient survival. MELK is aberrantly reactivated in cancer stem cells, thereby provid-ing a growth advantage for neoplastic cells and derived tumor progression. so MELK is a potential therapeutic tar-get in cancers. This paper will summarize the current knowledge of functions and mechanisms of MELK and its re-search development in carcinoma.
Maternal embryonic leucine zipper kinase(MELK) is a cell cycle-dependent protein kinase, which be-longs to the Snf1/AMPK family of serine-threonine kinases.Unlike most members of this family only functioningin cell survival under metabolically environmental stress, MELK participates in diverse processes, including cell cy-cle, cell proliferation, apoptosis, RNA processing, and embryonic development. The overexpression of MELK in vari-ous cancers results in poor patient survival. MELK is aberrantly reactivated in cancer stem cells, thereby provid-ing a growth advantage for neoplastic cells and derived tumor progression. so MELK is a potential therapeutic tar-get in cancers. This paper will summarize the current knowledge of functions and mechanisms of MELK and its re-search development in carcinoma.
引文
[1]Heyer B S,Warsowe J,Solter D,et al.New member of the Snf1/AMPK kinase family,Melk,is expressed in the mouse egg and preimplantation embryo[J].Mol Reprod Dev,1997,47(2):148-156.
[2]Gil M,Yang Y,Lee Y,et al.Cloning and expression of a c DNA encoding a novel protein serine/threonine kinase predominantly expressed in hematopoietic cells[J].Gene,1997,195(2):295-301.
[3]Blot J,Chartrain I,Roghi C,et al.Cell cycle regulation of p Eg3,a new Xenopus protein kinase of the KIN1/PAR-1/MARK family[J].Dev Biol,2002,241(2):327-338.
[4]Heyer B S,Kochanowski H,Solter D.Expression of Melk,a new protein kinase,during early mouse development[J].Dev Dyn,1999,215(4):344-351.
[5]Marie S,Okamoto O,Uno M,et al.Maternal embryonic leucine zipper kinase transcript abundance correlates with malignancy grade in human astrocytomas[J].Int J Cancer,2008,122(4):807-815.
[6]Liu J,Cao L,Chen J C,et al.Bmi1 regulates mitochondrial function and the DNA damage response pathway[J].Nature,2009,459(7245):387-392.
[7]Pickard M R,Green A R,Ellis I O,et al.Dysregulated expression of Fau and MELK is associated with poor prognosis in breast cancer[J].Breast Cancer Res,2009,11(4):R60.
[8]Pickard M R,Green A R,Ellis I O,et al.Dysregulated expression of Fau and MELK is associated with poor prognosis in breast cancer[J].Breast Cancer Res,2009,11(4):R60.
[9]Hebbard L,Maurer J,Miller A,et al.Maternal embryonic leucine zipper kinase is upregulated and required in mammary tumor-initiating cells in vivo[J].Cancer Res,2010,70(21):8863-8873.
[10]Nakano I,Masterman-Smith M,Saigusa K,et al.Maternal embryonic leucine zipper kinase is a key regulator of the proliferation of malignant brain tumors,including brain tumor stem cells[J].J Neurosci Res,2008,86(1):48-60.
[11]Saito R,Nakauchi H,Watanabe S.Serine/threonine kinase,Melk,regulates proliferation and glial differentiation of retinal progenitor cells[J].Cancer Sci,2012,103(1):42-49.
[12]Gray D,Jubb A,Hogue D,et al.Maternal embryonic leucine zipper kinase/murine protein serine-threonine kinase 38 is a promising therapeutic target for multiple cancers[J].Cancer Res,2005,65(21):9751-9761.
[13]Moravcevic K,Mendrola J M,Schmitz K R,et al.Kinase associated-1 domains drive MARK/PAR1 kinases to membrane targets by binding acidic phospholipids[J].Cell,2010,143(6):966-977.
[14]Jaleel M,Villa F,Deak M,et al.The ubiquitin-associated domain of AMPK-related kinases regulates conformation and LKB1-mediated phosphorylation and activation[J].Biochem J,2006,394:545-555.
[15]Murphy J M,Korzhnev D M,Ceccarelli D F,et al.Conformational instability of the MARK3 UBA domain compromises ubiquitin recognition and promotes interaction with the adjacent kinase domain[J].Proc Natl Acad Sci USA,2007,104(36):14336-14341.
[16]Lizcano J M,Goransson O,Toth R,et al.LKB1 is a master kinase that activates 13 kinases of the AMPK subfamily,including MARK/PAR-1[J].EMBO J,2004,23(4):833-843.
[17]Beullens M,Vancauwenbergh S,Morrice N,et al.Substrate specificity and activity regulation of protein kinase MELK[J].J Biol Chem,2005,280(48):40003-40011.
[18]Niu X P,Renshaw-Gegg L,Miller L,et al.Bipartite determinants of DNA-binding specificity of plant basic leucine zipper proteins[J].Plant Mol Biol,1999,41(1):1-13.
[19]Lamb P,Mc Knight S L,Diversity and specificity in transcriptional regulation:the benefits of heterotypic dimerization[J].Trends Biochem Sci,1991,16(11):417-422.
[20]Nakano I,Paucar A A,Bajpai R,et al.Maternal embryonic leucine zipper kinase(MELK)regulates multipotent neural progenitor proliferation[J].J Cell Biol,2005,170(3):413-427.
[21]Lin M,Park J,Nishidate T,et al.Involvement of maternal embryonic leucine zipper kinase(MELK)in mammary carcinogenesis through interaction with Bcl-G,a pro-apoptotic member of the Bcl-2 family[J].Breast Cancer Res,2007,9(1):R17.
[22]Davezac N,Baldin V,Blot J,et al.Human p Eg3 kinase associates with and phosphorylates CDC25B phosphatase:a potential role for p Eg3 in cell cycle regulation[J].Oncogene,2002,21(50):7630-7641.
[23]Jung H,Seong H A,Ha H.Murine protein Serine/Threonine kinase 38 activates apoptosis signal-regulating kinase 1 via Thr(838)phosphorylation[J].J Biol Chem,2008,283(50):34541-34553.
[24]Vulsteke V,Beullens M,Boudrez A,et al.Inhibition of spliceosome assembly by the cell cycle-regulated protein kinase MELK and involvement of splicing factor NIPP1[J].J Biol Chem,2004,279(10):8642-8647.
[25]Chung S,Suzuki H,Miyamoto T,et al.Development of an orally-administrative MELK-targeting inhibitor that suppresses the growth of various types of human cancer[J].Oncotarget,2012,3(12):1629-1640.
[26]Heyer B S,Warsowe J,Solter D,et al.New member of the Snf1/AMPK kinase family,Melk,is expressed in the mouse egg and preimplantation embryo[J].Mol Reprod Dev,1997,47(2):148-156.
[27]Terskikh A V,Easterday M C,Li L,et al.From hematopoiesis to neuropoiesis:evidence of overlapping genetic programs[J].Proc Natl Acad Sci USA,2001,98(14):7934-7939.
[28]Le Page Y,Chartrain I,Badouel C,et al.A functional analysis of MELK in cell division reveals a transition in the mode of cytokinesis during Xenopus development[J].J Cell Sci,2011,124(6):958-968.
[29]Nakano I,Joshi K,Visnyei K,et al.Siomycin A targets brain tumor stem cells partially through a MELK-mediated pathway[J].Neuro Oncol,2011,13(6):622-634.
[30]Jiang P,Zhang D.Maternal embryonic leucine zipper kinase(MELK):a novel regulator in cell cycle control,embryonic development,and cancer[J].Int J Mol Sci,2013,14(11):21551-21560.
[31]Seong H A,Kim K T,Ha H.Enhancement of B-MYB transcriptional activity by ZPR9,a novel zinc finger protein[J].J Biol Chem,2003,278(11):9655-9662.
[32]Seong H A,Ha H.Murine protein Serine-Threonine kinase38 activates p53 function through Ser(15)phosphorylation[J].J Biol Chem,2012,287(25):20797-20810.
[33]Seong H A,Jung H,Ha H.Murine protein Serine/Threonine kinase 38 stimulates TGF-beta signaling in a kinase-dependent manner via direct phosphorylation of Smad proteins[J].J Biol Chem,2010,285(40):30959-30970.
[34]Wang C,Liu M,Riojas R A,et al.Protein kinase C theta(PKC theta)-dependent phosphorylation of PDK1 at Ser(504)and Ser(532)contributes to palmitate-induced insulin resistance[J].J Biol Chem,2009,284(4):2038-2044.
[35]Seong H A,Jung H,Ichijo H,et al.Reciprocal negative regulation of PDK1 and ASK1 signaling by direct interaction and phosphorylation[J].J Biol Chem,2010,285(4):2397-2414.
[36]Du T,Qu Y,Li J,et al.Maternal embryonic leucine zipper kinase enhances gastric cancer progression via the FAK/Paxillin pathway[J].Mol Cancer,2014,13:100.
[37]Badouel C,Koerner R,Frank-Vaillant M,et al.M-phase MELK activity is regulated by MPF and MAPK[J].Cell Cycle,2006,5(8):883-889.
[38]Chung S,Nakamura Y.MELK inhibitor,novel molecular targeted therapeutics for human cancer stem cells[J].Cell Cycle,2013,12(11):1655-1656.
[39]Choi S,Ku J,Resistance of colorectal cancer cells to radiation and 5-FU is associated with MELK expression[J].Biochem Biophys Res Commun,2011,412(2):207-213.
[40]Nakano I,Joshi K,Visnyei K,et al.Siomycin A targets brain tumor stem cells partially through a MELK-mediated pathway[J].Neuro Oncol,2011,13(6):622-634.
[41]Chung S Y,Suzuki H,Miyamoto T,et al.Development of an orally-administrative MELK-targeting inhibitor that suppresses the growth of various types of human cancer[J].Oncotarget,2012,3(12):1629-1640.
[2]Gil M,Yang Y,Lee Y,et al.Cloning and expression of a c DNA encoding a novel protein serine/threonine kinase predominantly expressed in hematopoietic cells[J].Gene,1997,195(2):295-301.
[3]Blot J,Chartrain I,Roghi C,et al.Cell cycle regulation of p Eg3,a new Xenopus protein kinase of the KIN1/PAR-1/MARK family[J].Dev Biol,2002,241(2):327-338.
[4]Heyer B S,Kochanowski H,Solter D.Expression of Melk,a new protein kinase,during early mouse development[J].Dev Dyn,1999,215(4):344-351.
[5]Marie S,Okamoto O,Uno M,et al.Maternal embryonic leucine zipper kinase transcript abundance correlates with malignancy grade in human astrocytomas[J].Int J Cancer,2008,122(4):807-815.
[6]Liu J,Cao L,Chen J C,et al.Bmi1 regulates mitochondrial function and the DNA damage response pathway[J].Nature,2009,459(7245):387-392.
[7]Pickard M R,Green A R,Ellis I O,et al.Dysregulated expression of Fau and MELK is associated with poor prognosis in breast cancer[J].Breast Cancer Res,2009,11(4):R60.
[8]Pickard M R,Green A R,Ellis I O,et al.Dysregulated expression of Fau and MELK is associated with poor prognosis in breast cancer[J].Breast Cancer Res,2009,11(4):R60.
[9]Hebbard L,Maurer J,Miller A,et al.Maternal embryonic leucine zipper kinase is upregulated and required in mammary tumor-initiating cells in vivo[J].Cancer Res,2010,70(21):8863-8873.
[10]Nakano I,Masterman-Smith M,Saigusa K,et al.Maternal embryonic leucine zipper kinase is a key regulator of the proliferation of malignant brain tumors,including brain tumor stem cells[J].J Neurosci Res,2008,86(1):48-60.
[11]Saito R,Nakauchi H,Watanabe S.Serine/threonine kinase,Melk,regulates proliferation and glial differentiation of retinal progenitor cells[J].Cancer Sci,2012,103(1):42-49.
[12]Gray D,Jubb A,Hogue D,et al.Maternal embryonic leucine zipper kinase/murine protein serine-threonine kinase 38 is a promising therapeutic target for multiple cancers[J].Cancer Res,2005,65(21):9751-9761.
[13]Moravcevic K,Mendrola J M,Schmitz K R,et al.Kinase associated-1 domains drive MARK/PAR1 kinases to membrane targets by binding acidic phospholipids[J].Cell,2010,143(6):966-977.
[14]Jaleel M,Villa F,Deak M,et al.The ubiquitin-associated domain of AMPK-related kinases regulates conformation and LKB1-mediated phosphorylation and activation[J].Biochem J,2006,394:545-555.
[15]Murphy J M,Korzhnev D M,Ceccarelli D F,et al.Conformational instability of the MARK3 UBA domain compromises ubiquitin recognition and promotes interaction with the adjacent kinase domain[J].Proc Natl Acad Sci USA,2007,104(36):14336-14341.
[16]Lizcano J M,Goransson O,Toth R,et al.LKB1 is a master kinase that activates 13 kinases of the AMPK subfamily,including MARK/PAR-1[J].EMBO J,2004,23(4):833-843.
[17]Beullens M,Vancauwenbergh S,Morrice N,et al.Substrate specificity and activity regulation of protein kinase MELK[J].J Biol Chem,2005,280(48):40003-40011.
[18]Niu X P,Renshaw-Gegg L,Miller L,et al.Bipartite determinants of DNA-binding specificity of plant basic leucine zipper proteins[J].Plant Mol Biol,1999,41(1):1-13.
[19]Lamb P,Mc Knight S L,Diversity and specificity in transcriptional regulation:the benefits of heterotypic dimerization[J].Trends Biochem Sci,1991,16(11):417-422.
[20]Nakano I,Paucar A A,Bajpai R,et al.Maternal embryonic leucine zipper kinase(MELK)regulates multipotent neural progenitor proliferation[J].J Cell Biol,2005,170(3):413-427.
[21]Lin M,Park J,Nishidate T,et al.Involvement of maternal embryonic leucine zipper kinase(MELK)in mammary carcinogenesis through interaction with Bcl-G,a pro-apoptotic member of the Bcl-2 family[J].Breast Cancer Res,2007,9(1):R17.
[22]Davezac N,Baldin V,Blot J,et al.Human p Eg3 kinase associates with and phosphorylates CDC25B phosphatase:a potential role for p Eg3 in cell cycle regulation[J].Oncogene,2002,21(50):7630-7641.
[23]Jung H,Seong H A,Ha H.Murine protein Serine/Threonine kinase 38 activates apoptosis signal-regulating kinase 1 via Thr(838)phosphorylation[J].J Biol Chem,2008,283(50):34541-34553.
[24]Vulsteke V,Beullens M,Boudrez A,et al.Inhibition of spliceosome assembly by the cell cycle-regulated protein kinase MELK and involvement of splicing factor NIPP1[J].J Biol Chem,2004,279(10):8642-8647.
[25]Chung S,Suzuki H,Miyamoto T,et al.Development of an orally-administrative MELK-targeting inhibitor that suppresses the growth of various types of human cancer[J].Oncotarget,2012,3(12):1629-1640.
[26]Heyer B S,Warsowe J,Solter D,et al.New member of the Snf1/AMPK kinase family,Melk,is expressed in the mouse egg and preimplantation embryo[J].Mol Reprod Dev,1997,47(2):148-156.
[27]Terskikh A V,Easterday M C,Li L,et al.From hematopoiesis to neuropoiesis:evidence of overlapping genetic programs[J].Proc Natl Acad Sci USA,2001,98(14):7934-7939.
[28]Le Page Y,Chartrain I,Badouel C,et al.A functional analysis of MELK in cell division reveals a transition in the mode of cytokinesis during Xenopus development[J].J Cell Sci,2011,124(6):958-968.
[29]Nakano I,Joshi K,Visnyei K,et al.Siomycin A targets brain tumor stem cells partially through a MELK-mediated pathway[J].Neuro Oncol,2011,13(6):622-634.
[30]Jiang P,Zhang D.Maternal embryonic leucine zipper kinase(MELK):a novel regulator in cell cycle control,embryonic development,and cancer[J].Int J Mol Sci,2013,14(11):21551-21560.
[31]Seong H A,Kim K T,Ha H.Enhancement of B-MYB transcriptional activity by ZPR9,a novel zinc finger protein[J].J Biol Chem,2003,278(11):9655-9662.
[32]Seong H A,Ha H.Murine protein Serine-Threonine kinase38 activates p53 function through Ser(15)phosphorylation[J].J Biol Chem,2012,287(25):20797-20810.
[33]Seong H A,Jung H,Ha H.Murine protein Serine/Threonine kinase 38 stimulates TGF-beta signaling in a kinase-dependent manner via direct phosphorylation of Smad proteins[J].J Biol Chem,2010,285(40):30959-30970.
[34]Wang C,Liu M,Riojas R A,et al.Protein kinase C theta(PKC theta)-dependent phosphorylation of PDK1 at Ser(504)and Ser(532)contributes to palmitate-induced insulin resistance[J].J Biol Chem,2009,284(4):2038-2044.
[35]Seong H A,Jung H,Ichijo H,et al.Reciprocal negative regulation of PDK1 and ASK1 signaling by direct interaction and phosphorylation[J].J Biol Chem,2010,285(4):2397-2414.
[36]Du T,Qu Y,Li J,et al.Maternal embryonic leucine zipper kinase enhances gastric cancer progression via the FAK/Paxillin pathway[J].Mol Cancer,2014,13:100.
[37]Badouel C,Koerner R,Frank-Vaillant M,et al.M-phase MELK activity is regulated by MPF and MAPK[J].Cell Cycle,2006,5(8):883-889.
[38]Chung S,Nakamura Y.MELK inhibitor,novel molecular targeted therapeutics for human cancer stem cells[J].Cell Cycle,2013,12(11):1655-1656.
[39]Choi S,Ku J,Resistance of colorectal cancer cells to radiation and 5-FU is associated with MELK expression[J].Biochem Biophys Res Commun,2011,412(2):207-213.
[40]Nakano I,Joshi K,Visnyei K,et al.Siomycin A targets brain tumor stem cells partially through a MELK-mediated pathway[J].Neuro Oncol,2011,13(6):622-634.
[41]Chung S Y,Suzuki H,Miyamoto T,et al.Development of an orally-administrative MELK-targeting inhibitor that suppresses the growth of various types of human cancer[J].Oncotarget,2012,3(12):1629-1640.