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Int. J. Mol. Sci. 2013, 14(11), 21551-21560; doi:10.3390/ijms141121551
Abstract: Maternal embryonic leucine zipper kinase (MELK) functions as a modulator of intracellular signaling and affects various cellular and biological processes, including cell cycle, cell proliferation, apoptosis, spliceosome assembly, gene expression, embryonic development, hematopoiesis, and oncogenesis. In these cellular processes, MELK functions by binding to numerous proteins. In general, the effects of multiple protein interactions with MELK are oncogenic in nature, and the overexpression of MELK in kinds of cancer provides some evidence that it may be involved in tumorigenic process. In this review, our current knowledge of MELK function and recent discoveries in MELK signaling pathway were discussed. The regulation of MELK in cancers and its potential as a therapeutic target were also described.
According to studies on oncogenic signal transduction pathways, targeted therapies have made great progress in cancer treatment, whereas standard chemotherapy alone has failed to improve treatment outcome. In this paper, maternal embryonic leucine zipper kinase (MELK), a potential therapeutic target that is possibly involved in a tumorigenic process, was described. MELK, also known as murine protein serine/threonine kinase 38 (MPK38)  and Eg3 protein (pEg3) , was originally identified as a signal transduction factor by Gil et al. and Heyer et al. almost simultaneously [1,3]. MELK is also a cell cycle-dependent protein kinase that belongs to the KIN1/PAR-1/MARK family [2,4,5]. Unlike most members of this family only functioning in cell survival under metabolically challenging conditions [6–9], MELK participates in diverse processes, including cell cycle , cell proliferation , apoptosis [11,12], RNA processing , and embryonic development [3,14–16]. Furthermore, MELK is involved in multiple protein interactions that affect many stages of tumorigenesis . Thus, this gene is potentially an effective therapeutic target.
2. MELK as a Regulator of Cell Fate
MELK is initially cloned in oocytes and detected both in normal tissues and in cancer cells. Evidence has shown that MELK is expressed by multipotent neural progenitors derived from different ages and necessary for the proliferation of such progenitors in vitro, thereby influencing their ability to form neurospheres, which indicate self-regeneration . Previous studies have strongly indicated that MELK, unlike other KIN1/PAR-1/MARK family members, regulates cell cycle rather than cell survival. MELK is also required in the transition of proliferative glial fibrillary acidic protein (GFAP)-positive progenitor cells to highly proliferative GFAP-negative cells in vitro. These data have validated the important function of MELK in neural progenitor biology . MELK is also expressed in proliferating myoblasts  and mammary progenitors , suggesting that MELK is commonly expressed in tissue-specific progenitor cells. A previous study using mice in various developmental stages as a model shows that the expression levels of MELK gene in retinal progenitor cells is positively correlated with their proliferative activities in mice; MELK also participates in the differentiation of glial cells , suggesting that MELK has multiple functions in retinal development.
In Caenorhabditis elegans, PAR-1-like gene (PIG-1) is identified as a worm ortholog of MELK. It is reported that PIG-1 and cell death gene-3 (CED-3) double mutants result in nearly 100% of lineages producing extra HSN and PHB neurons, leading to dramatically stronger programmed cell death than either single mutant, which suggests that PIG-1 acts at least partly in parallel to the canonical cell death pathway . PIG-1 also regulates cell size asymmetry and asymmetric neuroblast divisions by controlling neuroblast polarity .
MELK physically interacts with apoptosis signal-regulating kinase 1 (ASK1), and the activity of ASK1 is either positively or negatively regulated by its interacting molecules, including tumor necrosis receptor-associated factor , Daxx , JNK/stress-activated protein kinase-associated protein 1/JNK-interacting protein 3 , thioredoxin [25,26], glutaredoxin , heat shock protein 72 , Raf-1 , Akt/PKB , PP5 , and 14-3-3 protein . MELK, as an upstream kinase of ASK1, phosphorylates threonine 838 in an activation loop of human ASK1, thereby stimulating ASK1 kinase activity. Interestingly, this interaction enhances JNK-mediated transactivation and H2O2-induced apoptosis . MELK also physically interacts with p53 and enhances of p53-dependent apoptosis and cell cycle arrest . Therefore, MELK is considered as a regulator of cell proliferation, differentiation, and apoptosis.
3. MELK Is Involved in Embryonic Development
Preliminary RT-PCR data have shown that MELK is specifically and highly expressed in an ovulated egg and during early mouse development . MELK transcripts are barely observed in two-cell stage embryos, but such transcripts are easily detectable in ovulated mouse eggs and increase in later developmental stages. Like other transcripts at the same developmental stage, MELK transcripts accumulate from an eight-cell stage to a blastocyst stage . In contrast to MELK transcripts, MELK proteins remain detectable throughout pre-implantation development. The presence of MELK protein in the zygote and two-cell stage embryos is likely due to a protein translated from maternal mRNA as observed in E-cadherin . MELK possibly functions as a cytoplasmic serine/threonine kinase to modify other proteins post-translationally at this time, thereby influencing further embryonic development .
Further studies have demonstrated that MELK is expressed in tissues containing normal progenitor cells  and in adult brain progenitor cells [34,35]. Knockdown of a MELK-like gene product in zebra fish has indicated that this product may function in primitive hematopoiesis .
MELK is associated with anillin, an important cytokinetic protein, and two other proteins co-localized at the equatorial cortex of Xenopus. Furthermore, a developmentally regulated transition involving Xenopus MELK (xMELK) occurs in cytokinesis during early embryogenesis .
4. MELK in Cancer
Serine/threonine kinases represent a suitable protein class for targeted therapies in cancer. MELK overexpression has been detected in various human tumors, suggesting that MELK is a significant contributor to tumorigenesis (Table 1). An increase in MELK expression is described in more aggressive forms of astrocytoma, breast cancer, melanoma, and glioblastoma [19,37–39]. Considering the results of preclinical studies, MELK is described as a potential anticancer target in diverse tumor entities .
MELK is important in oncogenesis as first emphasized in a previous finding, in which MELK expression is increased in tumor-derived progenitor cells and in cancers of non-differentiated cells [40,41,43]. For instance, MELK is required in cells that initiate mammary tumors . MELK is also highly expressed in various cell lines established from colorectal carcinoma . Furthermore, MELK is associated with anti-apoptotic activities of breast cancer cells by interacting with Bcl-G, a pro-apoptotic member of the Bcl-2 family [11,46]. Overexpression of MELK suppresses Bcl-G-induced apoptosis, which promotes mammary carcinogenesis  and results in poor patient survival in breast cancer and glioblastoma multiforms [19,47]. MELK may also function as a therapeutic target associated with the resistance of rectal cancer to chemoradiotherapy .
MELK knockdown decreases the transformed phenotype of multiple tumor cell lines as determined by in vivo xenograft assays as well as in vitro proliferation and anchorage-independent growth . Thiazole antibiotic siomycin A is identified as a potent inhibitor of MELK expression. The treatment of glioblastoma with siomycin A inhibits tumor growth in vivo. In particular, treatment of glioblastoma-derived brain tumor stem cells with siomycin A promotes self-regeneration, decreases invasion, and induces apoptosis . MELK is aberrantly reactivated in cancer stem cells, thereby providing a growth advantage for neoplastic cells and derived tumor progression [44,47]. MELK expression in normal progenitor cells indicates that the dysregulation of MELK may cause carcinogenesis in various cell types .
These data have suggested that the overexpression of MELK contributes to the development of tumors, but the inhibition of MELK sufficiently affects proliferation and other properties of tumors. Further investigation on MELK as a cancer therapeutic target is needed.
5. Proteins Interacting with MELK
Preliminary evidence has indicated that MELK is involved in various cellular processes by binding to numerous proteins, thereby resulting in cell cycle regulation, cell proliferation, apoptosis, spliceosome assembly, gene expression, hematopoiesis, embryonic development, and oncogenesis [12,13,36,40,49,50]. Proteins that interact with MELK are listed in Table 2.
MELK can regulate numerous proteins via interaction and phosphorylation. MELK phosphorylates and binds tightly to the zinc finger-like protein 9 (ZPR9), and causes its nuclear accumulation [51,52]. In the nucleus, ZPR9 interacts with the transcription factor v-MYB avian myeloblastosis viral oncogene homolog 2 (B-Myb), a regulator of cell proliferation and differentiation, and enhances its transcriptional activity . MELK also interacts with nuclear inhibitor of protein Ser/Thr phosphatase-1 (NIPP1), a transcription and splicing factor, by binding of a threonine-phosphorylated motif to FHA domain of NIPP1. Furthermore, the MELK-NIPP1 interaction is significantly increased during mitosis, resulting in an inhibition of pre-mRNA splicing . MELK physically interacts with and phosphorylates PDK1 at threonine 354, thereby inhibiting its activity and function. CDC25B is a protein-tyrosine phosphatase that triggers mitosis by activating protein kinase CDK1. MELK can also phosphorylate and interact with CDC25B, by which the G2 accumulation induced by MELK overexpression in cultured cells is counteracted . MELK also physically interacts with p53 in vivo and in vitro. It phosphorylates Ser15 in the amino-terminal transactivation domain of p53, thereby stimulating p53 activity. This interaction contributes to the enhancement of p53-dependent apoptosis and cell cycle arrest by modulating the stability of p53 . Overexpression of MELK significantly increases the MAPKKK activity of ASK1 by directly interacting with and phosphorylating ASK1, which stimulates the activation of ASK1-mediated signaling to JNK and p38 kinases. Such overexpression of MELK also results in a significant increase in H2O2-induced apoptosis by interacting with ASK1 . Therefore, the MELK-ASK1 interaction may provide a molecular basis for several proposed MELK functions. Bcl-G, a pro-apoptotic factor, has been the focus of studies recently. It is identified as an important target for MELK, which is associated with resistance to apoptosis . The modification of BCL-G provides an attractive mechanism of the observed pro-survival effects of MELK . MELK positively regulates transforming growth factor-β (TGF-β) transcription by directly interacting with and phosphorylating Smad proteins (Smad2, -3, -4, and -7), which is required for TGF-β-mediated biological functions, such as apoptosis and cell growth arrest . Therefore, these findings provided some support for the regulation of cell cycle, cell proliferation, and apoptosis by MELK. Further, these results may also support the conceptual premise that MELK functions in the development of various tissues by maintaining the balance between cell proliferation and survival.
MELK activity is also regulated via phosphorylation by other proteins. For instance, MELK can be phosphorylated by mitosis-promoting factor (MPF) and MAPK during M phase. Threonine 414, threonine 449, threonine 451, threonine 481, and serine 498 phosphorylation sites in xMELK extract are identified in its egg at the M phase, whereas 14 residues are phosphorylated in recombinant human MELK (hMELK) protein expressed and purified from bacteria. Experiments performed in vivo have suggested that xMELK phosphorylation is involved in MPF and MAPK pathways. MPF and MAPK directly phosphorylate xMELK and enhance its kinase activity in vitro. In addition, the specific phosphorylation of threonine 449, threonine 451, and threonine 481 in M phase is detected during Xenopus oocyte maturation in embryos and in Xenopus cultured cells .
Thus, many of these interactions result in aberrant signaling involved in cell cycle progression, TGF-β signaling, embryonic development, ASK1-mediated signaling, and apoptosis. Some of these interactions are often ambiguous, and the function of MELK is only partially clear. Further studies should be conducted to identify the exact mechanisms involved and define the function of MELK in normal developmental processes and tumorigenesis.
6. Conclusions and Perspectives
Multiple functions of MELK affect numerous proteins and signaling pathways through protein-protein interactions. In general, the results of these interactions are oncogenic. Overexpression of MELK in various human cancers suggests its importance in carcinogenesis. However, the exact function of MELK in oncogenic processes and in other functions remains partially understood. Future studies should determine whether or not MELK contributes to tumorigenesis via a specific interaction or multiple interactions. Furthermore, because protein-protein interactions include direct and indirect interactions, future studies should elucidate whether or not these interactions are dependent on the presence of MELK.
The physiological importance of MELK in cancer is highlighted because of its overexpression in various cancers. However, the molecular mechanism by which MELK is involved in a myriad of protein interactions remains unclear. No particular protein domain has been identified in these proteins that link them with one another. Thus, the activation mechanisms should be elucidated to understand the regulation of the functions of MELK.
Although information about MELK remains unclear, its overexpression is involved in cell cycle regulation and cancer development. Further investigation of MELK as a therapeutic target may lead to the development of a powerful cancer therapeutic target in various tumors.
|Pediatric brain tumor||ND|||
|Colon tumor||Therapeutic target|||
|Astrocytomas||Therapeutic target to treat human glioblastomas|||
|Breast cancer||Interacting with Bcl-G and associated with poor prognosis||[11,19]|
|Melanoma||Mitosis and protein phosphorylation|||
|Rectal cancer||Contributed to radioresistance and chemoresistance of SNU-503|||
Abbreviation: ND, not determined.
|ZPR9||A physiological substrate of MELK kinase in vivo||Resulting in the nuclear accumulation of ZPR9||[51,52]|
|NIPP1||Transcription and splicing factor, inhibitor of protein Ser/Thr phosphatase-1||Regulating cell cycle progression through pre-mRNA processing|||
|Cdc25B||Protein-tyrosine phosphatase||Inducing cell accumulation in G2|||
|PDK1||An enzyme responsible for the phosphorylation of the activation loop of Akt/PKB||Inhibiting activity and function of PDK1||[53,54]|
|P53||Tumor suppressor||Enhancing p53-dependent apoptosis and cell cycle arrest by modulating the stability of p53|||
|Smad proteins (Smad2, -3, -4, and -7)||Intracellular signaling mediators of the TGF-β signaling pathway||Regulating Smad activities involved in TGF-β signaling|||
|ASK1||Mitogen-activated protein kinase kinase kinase||Enhancing of JNK-mediated transactivation and H2O2-induced apoptosis|||
|Bcl-G||A pro-apoptotic factor||Resistance to apoptosis|||
|MPF||Mitosis-promoting factor||Phosphorylating MELK and enhancing its kinase activity|||
|MAPK||Mitogen-activated protein kinase||Phosphorylating MELK and enhancing its kinase activity|||
This study was supported by the National Natural Science Foundation of China (Grant No. 31072115) and a preparatory project sponsored by the National Ministry of Science and Technology of China of the First Batch in the Basic Research Category of the National Program of Science & Technology in the Field of Countryside 2011–2015 (Preparatory Project No. NC2010CD0178).
Conflicts of Interest
The authors declare no conflict of interest.
- Gil, M.; Yang, Y.; Lee, Y.; Choi, I.; Ha, H. Cloning and expression of a cdna encoding a novel protein serine/threonine kinase predominantly expressed in hematopoietic cells. Gene 1997, 195, 295–301. [Google Scholar]
- Blot, J.; Chartrain, I.; Roghi, C.; Philippe, M.; Tassan, J.P. Cell cycle regulation of peg3, a new xenopus protein kinase of the KIN1/PAR-1/MARK family. Dev. Biol 2002, 241, 327–338. [Google Scholar]
- Heyer, B.S.; Warsowe, J.; Solter, D.; Knowles, B.B.; Ackerman, S.L. New member of the SNF1/AMPK kinase family, melk, is expressed in the mouse egg and preimplantation embryo. Mol. Reprod. Dev 1997, 47, 148–156. [Google Scholar]
- Davezac, N.; Baldin, V.; Blot, J.; Ducommun, B.; Tassan, J.P. Human pEg3 kinase associates with and phosphorylates CDC25B phosphatase: A potential role for pEg3 in cell cycle regulation. Oncogene 2002, 21, 7630–7641. [Google Scholar]
- Tassan, J.P.; le Goff, X. An overview of the KIN1/PAR-1/MARK kinase family. Biol. Cell 2004, 96, 193–199. [Google Scholar]
- Kato, K.; Ogura, T.; Kishimoto, A.; Minegishi, Y.; Nakajima, N.; Miyazaki, M.; Esumi, H. Critical roles of amp-activated protein kinase in constitutive tolerance of cancer cells to nutrient deprivation and tumor formation. Oncogene 2002, 21, 6082–6090. [Google Scholar]
- Inoki, K.; Zhu, T.; Guan, K.L. TSC2 mediates cellular energy response to control cell growth and survival. Cell 2003, 115, 577–590. [Google Scholar]
- Suzuki, A.; Kusakai, G.; Kishimoto, A.; Lu, J.; Ogura, T.; Esumi, H. ARK5 suppresses the cell death induced by nutrient starvation and death receptors via inhibition of caspase 8 activation, but not by chemotherapeutic agents or uv irradiation. Oncogene 2003, 22, 6177–6182. [Google Scholar]
- Suzuki, A.; Kusakai, G.; Kishimoto, A.; Lu, J.; Ogura, T.; Lavin, M.F.; Esumi, H. Identification of a novel protein kinase mediating Akt survival signaling to the atm protein. J. Biol. Chem 2003, 278, 48–53. [Google Scholar]
- Nakano, I.; Paucar, A.A.; Bajpai, R.; Dougherty, J.D.; Zewail, A.; Kelly, T.K.; Kim, K.J.; Ou, J.; Groszer, M.; Imura, T.; et al. Maternal embryonic leucine zipper kinase (MELK) regulates multipotent neural progenitor proliferation. J. Cell Biol 2005, 170, 413–427. [Google Scholar]
- Lin, M.L.; Park, J.H.; Nishidate, T.; Nakamura, Y.; Katagiri, T. 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. Breast Cancer Res 2007, 9, R17. [Google Scholar]
- Jung, H.; Seong, H.A.; Ha, H. Murine protein serine/threonine kinase 38 activates apoptosis signal-regulating kinase 1 via Thr 838 phosphorylation. J. Biol. Chem 2008, 283, 34541–34553. [Google Scholar]
- Vulsteke, V.; Beullens, M.; Boudrez, A.; Keppens, S.; van Eynde, A.; Rider, M.H.; Stalmans, W.; Bollen, M. Inhibition of spliceosome assembly by the cell cycle-regulated protein kinase MELK and involvement of splicing factor NIPP1. J. Biol. Chem 2004, 279, 8642–8647. [Google Scholar]
- Kidder, G.M. The genetic program for preimplantation development. Dev. Genet 1992, 13, 319–325. [Google Scholar]
- Heyer, B.S.; Kochanowski, H.; Solter, D. Expression of MELK, a new protein kinase, during early mouse development. Dev. Dyn 1999, 215, 344–351. [Google Scholar]
- Le Page, Y.; Chartrain, I.; Badouel, C.; Tassan, J.P. A functional analysis of MELK in cell division reveals a transition in the mode of cytokinesis during xenopus development. J. Cell Sci 2011, 124, 958–968. [Google Scholar]
- Chung, S.; Suzuki, H.; Miyamoto, T.; Takamatsu, N.; Tatsuguchi, A.; Ueda, K.; Kijima, K.; Nakamura, Y.; Matsuo, Y. Development of an orally-administrative MELK-targeting inhibitor that suppresses the growth of various types of human cancer. Oncotarget 2012, 3, 1629–1640. [Google Scholar]
- Niesler, C.U.; Myburgh, K.H.; Moore, F. The changing AMPK expression profile in differentiating mouse skeletal muscle myoblast cells helps confer increasing resistance to apoptosis. Exp. Physiol 2007, 92, 207–217. [Google Scholar]
- Pickard, M.R.; Green, A.R.; Ellis, I.O.; Caldas, C.; Hedge, V.L.; Mourtada-Maarabouni, M.; Williams, G.T. Dysregulated expression of fau and MELK is associated with poor prognosis in breast cancer. Breast Cancer Res 2009, 11, R60. [Google Scholar]
- Saito, R.; Nakauchi, H.; Watanabe, S. Serine/threonine kinase, MELK, regulates proliferation and glial differentiation of retinal progenitor cells. Cancer Sci 2012, 103, 42–49. [Google Scholar]
- Cordes, S.; Frank, C.A.; Garriga, G. The C. elegans MELK ortholog pig-1 regulates cell size asymmetry and daughter cell fate in asymmetric neuroblast divisions. Development 2006, 133, 2747–2756. [Google Scholar]
- Nishitoh, H.; Saitoh, M.; Mochida, Y.; Takeda, K.; Nakano, H.; Rothe, M.; Miyazono, K.; Ichijo, H. ASK1 is essential for JNK/SAPK activation by TRAF2. Mol. Cell 1998, 2, 389–395. [Google Scholar]
- Chang, H.Y.; Nishitoh, H.; Yang, X.; Ichijo, H.; Baltimore, D. Activation of apoptosis signal-regulating kinase 1 (ASK1) by the adapter protein daxx. Science 1998, 281, 1860–1863. [Google Scholar]
- Matsuura, H.; Nishitoh, H.; Takeda, K.; Matsuzawa, A.; Amagasa, T.; Ito, M.; Yoshioka, K.; Ichijo, H. Phosphorylation-dependent scaffolding role of JSAP1/JIP3 in the ASK1-JNK signaling pathway. A new mode of regulation of the map kinase cascade. J. Biol. Chem 2002, 277, 40703–40709. [Google Scholar]
- Saitoh, M.; Nishitoh, H.; Fujii, M.; Takeda, K.; Tobiume, K.; Sawada, Y.; Kawabata, M.; Miyazono, K.; Ichijo, H. Mammalian thioredoxin is a direct inhibitor of apoptosis signal-regulating kinase (ASK) 1. EMBO J 1998, 17, 2596–2606. [Google Scholar]
- Liu, H.; Nishitoh, H.; Ichijo, H.; Kyriakis, J.M. Activation of apoptosis signal-regulating kinase 1 (ASK1) by tumor necrosis factor receptor-associated factor 2 requires prior dissociation of the Ask1 inhibitor thioredoxin. Mol. Cell Biol 2000, 20, 2198–2208. [Google Scholar]
- Song, J.J.; Rhee, J.G.; Suntharalingam, M.; Walsh, S.A.; Spitz, D.R.; Lee, Y.J. Role of glutaredoxin in metabolic oxidative stress. Glutaredoxin as a sensor of oxidative stress mediated by H2O2. J. Biol. Chem 2002, 277, 46566–46575. [Google Scholar]
- Park, H.S.; Cho, S.G.; Kim, C.K.; Hwang, H.S.; Noh, K.T.; Kim, M.S.; Huh, S.H.; Kim, M.J.; Ryoo, K.; Kim, E.K.; et al. Heat shock protein hsp72 is a negative regulator of apoptosis signal-regulating kinase 1. Mol. Cell Biol 2002, 22, 7721–7730. [Google Scholar]
- Kim, A.H.; Khursigara, G.; Sun, X.; Franke, T.F.; Chao, M.V. Akt phosphorylates and negatively regulates apoptosis signal-regulating kinase 1. Mol. Cell Biol 2001, 21, 893–901. [Google Scholar]
- Morita, K.; Saitoh, M.; Tobiume, K.; Matsuura, H.; Enomoto, S.; Nishitoh, H.; Ichijo, H. Negative feedback regulation of ASK1 by protein phosphatase 5 (pp5) in response to oxidative stress. EMBO J 2001, 20, 6028–6036. [Google Scholar]
- Zhang, L.; Chen, J.; Fu, H. Suppression of apoptosis signal-regulating kinase 1-induced cell death by 14-3-3 proteins. Proc. Natl. Acad. Sci. USA 1999, 96, 8511–8515. [Google Scholar]
- Seong, H.A.; Ha, H. Murine protein serine-threonine kinase 38 activates p53 function through ser15 phosphorylation. J. Biol. Chem 2012, 287, 20797–20810. [Google Scholar]
- Ohsugi, M.; Hwang, S.Y.; Butz, S.; Knowles, B.B.; Solter, D.; Kemler, R. Expression and cell membrane localization of catenins during mouse preimplantation development. Dev. Dyn 1996, 206, 391–402. [Google Scholar]
- Geschwind, D.H.; Ou, J.; Easterday, M.C.; Dougherty, J.D.; Jackson, R.L.; Chen, Z.; Antoine, H.; Terskikh, A.; Weissman, I.L.; Nelson, S.F.; et al. A genetic analysis of neural progenitor differentiation. Neuron 2001, 29, 325–339. [Google Scholar]
- Terskikh, A.V.; Easterday, M.C.; Li, L.; Hood, L.; Kornblum, H.I.; Geschwind, D.H.; Weissman, I.L. From hematopoiesis to neuropoiesis: Evidence of overlapping genetic programs. Proc. Natl. Acad. Sci. USA 2001, 98, 7934–7939. [Google Scholar]
- Saito, R.; Tabata, Y.; Muto, A.; Arai, K.; Watanabe, S. MELK-like kinase plays a role in hematopoiesis in the zebra fish. Mol. Cell Biol 2005, 25, 6682–6693. [Google Scholar]
- Liu, G.; Yuan, X.; Zeng, Z.; Tunici, P.; Ng, H.; Abdulkadir, I.R.; Lu, L.; Irvin, D.; Black, K.L.; Yu, J.S. Analysis of gene expression and chemoresistance of cd133+ cancer stem cells in glioblastoma. Mol. Cancer 2006, 5, 67. [Google Scholar]
- Ryu, B.; Kim, D.S.; Deluca, A.M.; Alani, R.M. Comprehensive expression profiling of tumor cell lines identifies molecular signatures of melanoma progression. PLoS One 2007, 2, e594. [Google Scholar]
- Marie, S.K.; Okamoto, O.K.; Uno, M.; Hasegawa, A.P.; Oba-Shinjo, S.M.; Cohen, T.; Camargo, A.A.; Kosoy, A.; Carlotti, C.G., Jr.; Toledo, S.; et al. Maternal embryonic leucine zipper kinase transcript abundance correlates with malignancy grade in human astrocytomas. Int. J. Cancer 2008, 122, 807–815. [Google Scholar]
- Gray, D.; Jubb, A.M.; Hogue, D.; Dowd, P.; Kljavin, N.; Yi, S.; Bai, W.; Frantz, G.; Zhang, Z.; Koeppen, H.; et al. Maternal embryonic leucine zipper kinase/murine protein serine-threonine kinase 38 is a promising therapeutic target for multiple cancers. Cancer Res 2005, 65, 9751–9761. [Google Scholar]
- Hemmati, H.D.; Nakano, I.; Lazareff, J.A.; Masterman-Smith, M.; Geschwind, D.H.; Bronner-Fraser, M.; Kornblum, H.I. Cancerous stem cells can arise from pediatric brain tumors. Proc. Natl. Acad. Sci. USA 2003, 100, 15178–15183. [Google Scholar]
- Choi, S.; Ku, J.L. Resistance of colorectal cancer cells to radiation and 5-fu is associated with MELK expression. Biochem. Biophys. Res. Commun 2011, 412, 207–213. [Google Scholar]
- Rhodes, D.R.; Yu, J.; Shanker, K.; Deshpande, N.; Varambally, R.; Ghosh, D.; Barrette, T.; Pandey, A.; Chinnaiyan, A.M. Large-Scale meta-analysis of cancer microarray data identifies common transcriptional profiles of neoplastic transformation and progression. Proc. Natl. Acad. Sci. USA 2004, 101, 9309–9314. [Google Scholar]
- Hebbard, L.W.; Maurer, J.; Miller, A.; Lesperance, J.; Hassell, J.; Oshima, R.G.; Terskikh, A.V. Maternal embryonic leucine zipper kinase is upregulated and required in mammary tumor-initiating cells in vivo. Cancer Res. 2010, 70, 8863–8873. [Google Scholar]
- Ku, J.L.; Shin, Y.K.; Kim, D.W.; Kim, K.H.; Choi, J.S.; Hong, S.H.; Jeon, Y.K.; Kim, S.H.; Kim, H.S.; Park, J.H.; et al. Establishment and characterization of 13 human colorectal carcinoma cell lines: Mutations of genes and expressions of drug-sensitivity genes and cancer stem cell markers. Carcinogenesis 2010, 31, 1003–1009. [Google Scholar]
- Guo, B.; Godzik, A.; Reed, J.C. Bcl-g, a novel pro-apoptotic member of the Bcl-2 family. J. Biol. Chem 2001, 276, 2780–2785. [Google Scholar]
- Nakano, I.; Masterman-Smith, M.; Saigusa, K.; Paucar, A.A.; Horvath, S.; Shoemaker, L.; Watanabe, M.; Negro, A.; Bajpai, R.; Howes, A.; et al. Maternal embryonic leucine zipper kinase is a key regulator of the proliferation of malignant brain tumors, including brain tumor stem cells. J. Neurosci. Res 2008, 86, 48–60. [Google Scholar]
- Nakano, I.; Joshi, K.; Visnyei, K.; Hu, B.; Watanabe, M.; Lam, D.; Wexler, E.; Saigusa, K.; Nakamura, Y.; Laks, D.R.; et al. Siomycin a targets brain tumor stem cells partially through a MELK-mediated pathway. Neuro Oncol 2011, 13, 622–634. [Google Scholar]
- Beullens, M.; Vancauwenbergh, S.; Morrice, N.; Derua, R.; Ceulemans, H.; Waelkens, E.; Bollen, M. Substrate specificity and activity regulation of protein kinase MELK. J. Biol. Chem 2005, 280, 40003–40011. [Google Scholar]
- 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. Biol. Chem 2010, 285, 30959–30970. [Google Scholar]
- Seong, H.A.; Gil, M.; Kim, K.T.; Kim, S.J.; Ha, H. Phosphorylation of a novel zinc-finger-like protein, ZPR9, by murine protein serine/threonine kinase 38 (MPK38). Biochem. J 2002, 361, 597–604. [Google Scholar]
- Seong, H.A.; Kim, K.T.; Ha, H. Enhancement of B-MYB transcriptional activity by ZPR9, a novel zinc finger protein. J. Biol. Chem 2003, 278, 9655–9662. [Google Scholar]
- Wang, C.; Liu, M.; Riojas, R.A.; Xin, X.; Gao, Z.; Zeng, R.; Wu, J.; Dong, L.Q.; Liu, F. Protein kinase c theta (PKCtheta)-dependent phosphorylation of PDK1 at Ser504 and Ser532 contributes to palmitate-induced insulin resistance. J. Biol. Chem 2009, 284, 2038–2044. [Google Scholar]
- Seong, H.A.; Jung, H.; Ichijo, H.; Ha, H. Reciprocal negative regulation of PDK1 and ASK1 signaling by direct interaction and phosphorylation. J. Biol. Chem 2010, 285, 2397–2414. [Google Scholar]
- Badouel, C.; Korner, R.; Frank-Vaillant, M.; Couturier, A.; Nigg, E.A.; Tassan, J.P. M-Phase MELK activity is regulated by MPF and MAPK. Cell Cycle 2006, 5, 883–889. [Google Scholar]
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