{"doi":"10.1074/jbc.m800987200","title":"Cdk5-mediated Phosphorylation of c-Myc on Ser-62 Is Essential in Transcriptional Activation of Cyclin B1 by Cyclin G1","abstract":null,"journal":"Journal of Biological Chemistry","year":2008,"id":592433,"datarank":3.061673606947212,"base_score":4.127134385045092,"endowment":4.127134385045092,"self_citation_contribution":0.6190701577567639,"citation_network_contribution":2.442603449190448,"self_endowment_contribution":0.6190701577567639,"citer_contribution":2.442603449190448,"corpus_percentile":null,"corpus_rank":null,"citation_count":61,"citer_count":61,"citers_with_citation_signal":55,"citers_with_endowment":55,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":147989,"name":"Joon Kim","orcid":null,"position":1,"is_corresponding":false},{"id":1515944,"name":"Sangwoo Bae","orcid":null,"position":2,"is_corresponding":false},{"id":1515945,"name":"Jae-Won Soh","orcid":null,"position":3,"is_corresponding":false},{"id":112287,"name":"Yun-Sil Lee","orcid":null,"position":4,"is_corresponding":false},{"id":1515943,"name":"Haeng Ran Seo","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Cdk5-mediated Phosphorylation of c-Myc on Ser-62 Is Essential in Transcriptional Activation of Cyclin B1 by Cyclin G1","abstract":"It has been reported previously that cyclin G1 enables cells to overcome radiation-induced G2 arrest and increased cell death and that these effects are mediated by transcriptional activation of cyclin B1. In this study, we further investigated the mechanism by which cyclin G1 transcriptionally activates cyclin B1. Deletion or point mutations within the cyclin B1 promoter region revealed that the c-Myc binding site (E-box) is necessary for cyclin G1-mediated transcriptional activation of cyclin B1 to occur. In addition, the kinase activity of Cdk5 was increased by cyclin G1 overexpression, and Cdk5 directly phosphorylated c-Myc on Ser-62. Furthermore, cyclin G1 mediated increased radiosensitivity, and radiation-induced M phase arrest was attenuated when RNA interference of Cdk5 was treated. Taken together, the results of this study indicate that Cdk5 activation in cells that overexpress cyclin G1 leads to c-Myc phosphorylation on Ser-62, which is responsible for cyclin G1-mediated transcriptional activation of cyclin B1. It has been reported previously that cyclin G1 enables cells to overcome radiation-induced G2 arrest and increased cell death and that these effects are mediated by transcriptional activation of cyclin B1. In this study, we further investigated the mechanism by which cyclin G1 transcriptionally activates cyclin B1. Deletion or point mutations within the cyclin B1 promoter region revealed that the c-Myc binding site (E-box) is necessary for cyclin G1-mediated transcriptional activation of cyclin B1 to occur. In addition, the kinase activity of Cdk5 was increased by cyclin G1 overexpression, and Cdk5 directly phosphorylated c-Myc on Ser-62. Furthermore, cyclin G1 mediated increased radiosensitivity, and radiation-induced M phase arrest was attenuated when RNA interference of Cdk5 was treated. Taken together, the results of this study indicate that Cdk5 activation in cells that overexpress cyclin G1 leads to c-Myc phosphorylation on Ser-62, which is responsible for cyclin G1-mediated transcriptional activation of cyclin B1. Cell cycle arrest in response to DNA damage occurs primarily at the G1/S and G2/M boundaries (1Hartwell L.H. Kastan M.B. Science. 1994; 266: 1821-1828Crossref PubMed Scopus (2316) Google Scholar, 2Kastan M.B. Lim D.S. Kim S.T. Yang D. Acta Oncol. 2001; 40: 686-688Crossref PubMed Scopus (67) Google Scholar), with G1/S arrest blocking entry of damaged DNA into the S phase and G2/M arrest prohibiting entry of damaged DNA into mitosis. Therefore, both the G1/S and G2/M checkpoints are important for maintaining genomic stability, as well as for maintaining the fidelity of transmission of intact genomes to cellular progeny (3Hartwell L. Cell. 1992; 71: 543-546Abstract Full Text PDF PubMed Scopus (737) Google Scholar, 4Paulovich A.G. Toczyski D.P. Hartwell L.H. Cell. 1997; 88: 315-321Abstract Full Text Full Text PDF PubMed Scopus (567) Google Scholar). The eventual target of the G2/M entry checkpoint is the mitotic kinase Cdc2-cyclin B1, which governs most of the processes involved in mitotic initiation and progression (5Hunt N. Adams S. Coxhead N. Sayer H. Murray C. Silverstone T. Soc. Psychiatry Psychiatr. Epidemiol. 1993; 28: 281-284Crossref PubMed Scopus (12) Google Scholar). Cyclin protein levels oscillate during the cell cycle, with B-type cyclins appearing during the S phase and accumulating in G2 and mitosis before disappearing during the transition from metaphase to anaphase. Synthesis of cyclin B1 during the cell cycle is regulated primarily at the transcriptional level (6Brandeis M. Hunt T. EMBO J. 1996; 15: 5280-5289Crossref PubMed Scopus (248) Google Scholar) by a cell cycle-dependent element (CDE) 3The abbreviations used are: CDE, cell cycle-dependent element; CHR, cell cycle gene homology region; GSK, glycogen synthase kinase; Cdk5, cyclin-dependent kinase 5; ERK, extracellular signal-regulated kinase; MEK, mitogen-activated protein kinase/extracellular signal-regulated kinase kinase; siRNA, small interfering RNA; Si-, transfected with siRNA; ChIP, chromatin immunoprecipitation; Gy, gray (unit of radiation); GST, glutathione S-transferase. and cell cycle gene homology region (CHR) tandem element (7Lange-zu Dohna C. Brandeis M. Berr F. Mossner J. Engeland K. FEBS Lett. 2000; 484: 77-81Crossref PubMed Scopus (48) Google Scholar). Transcription of Cdc25C, cyclin A, and the Cdc2 gene causes CDE/CHR elements to repress transcription during the early phases of the cell cycle; however, relief from this repression later in S and G2 leads to their expression (8Zwicker J. Lucibello F.C. Wolfraim L.A. Gross C. Truss M. Engeland K. Muller R. The EMBO journal. 1995; 14: 4514-4522Crossref PubMed Scopus (281) Google Scholar). Furthermore, although degradation by ubiquitin-mediated proteolysis leads to a large drop in cyclin B1 protein levels (6Brandeis M. Hunt T. EMBO J. 1996; 15: 5280-5289Crossref PubMed Scopus (248) Google Scholar, 9Hunt T. Luca F.C. Ruderman J.V. J. Cell Biol. 1992; 116: 707-724Crossref PubMed Scopus (203) Google Scholar, 10Townsley F.M. Ruderman J.V. Yeast. 1998; 14: 747-757Crossref PubMed Scopus (23) Google Scholar), it has been reported that an E-box is involved in the transcriptional regulation of cyclin B1 (11Cogswell J.P. Godlevski M.M. Bonham M. Bisi J. Babiss L. Mol. Cell. Biol. 1995; 15: 2782-2790Crossref PubMed Scopus (115) Google Scholar, 12Farina A. Gaetano C. Crescenzi M. Puccini F. Manni I. Sacchi A. Piaggio G. Oncogene. 1996; 13: 1287-1296PubMed Google Scholar). Moreover, a recent report has provided evidence that the cyclin B1 promoter is also subject to activation by c-Myc, as demonstrated by the binding of c-Myc to the activating E-box (CACGTG) of cyclin B1 (13Menssen A. Hermeking H. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 6274-6279Crossref PubMed Scopus (318) Google Scholar, 14Yin X.Y. Grove L. Datta N.S. Katula K. Long M.W. Prochownik E.V. Cancer Res. 2001; 61: 6487-6493PubMed Google Scholar). However, the exact upstream mechanisms that cause c-Myc to bind to the E-box of the cyclin B1 promoter region during cell cycle regulation have not yet been defined. An enhancer E-box can be defined as a transcriptional homograph, which is a short DNA element with the ability to dispense different transcriptional outputs depending upon the features of the sequence and cellular environment. For example, by recruiting the proto-oncogene c-Myc, an E-box can drive cells to become growth factor-independent, to speed through G1 of the cell cycle, to avoid differentiation, or to undergo apoptotic death (15Fuhrmann G. Rosenberger G. Grusch M. Klein N. Hofmann J. Krupitza G. Mutat. Res. 1999; 437: 205-217Crossref PubMed Scopus (47) Google Scholar, 16Littlewood T.D. Evan G.I. Adv. Dent. Res. 1990; 4: 69-79Crossref PubMed Scopus (33) Google Scholar). The perplexing diversity of E-box-dependent processes has fueled an intense search for trans-acting factors regulating a given E-box. Predictably, such efforts have resulted in an ever expanding list of transcription factors that can recognize E-box binding factors, including c-Myc, Arnt, Max, and MyoD (17Antonsson C. Arulampalam V. Whitelaw M.L. Pettersson S. Poellinger L. J. Biol. Chem. 1995; 270: 13968-13972Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar, 18Biben C. Kirschbaum B.J. Garner I. Buckingham M. Mol. Cell. Biol. 1994; 14: 3504-3513Crossref PubMed Scopus (25) Google Scholar, 19Huang G. Xiao X. Huang Y. Huang R. Journal of West China University of Medical Sciences. 1996; 27: 5-9Google Scholar). Temporal regulation of c-Myc protein accumulation is essential for normal cell proliferation to occur, and deregulation of the c-myc oncogene is often observed in human cancer (20Nesbit C.E. Tersak J.M. Prochownik E.V. Oncogene. 1999; 18: 3004-3016Crossref PubMed Scopus (974) Google Scholar). In addition, c-Myc protein overexpression can immortalize cells, reduce their growth factor requirements, promote cell cycle progression, and inhibit differentiation (21Claassen G.F. Hann S.R. Oncogene. 1999; 18: 2925-2933Crossref PubMed Scopus (110) Google Scholar, 22Henriksson M. Luscher B. Adv. Cancer Res. 1996; 68: 109-182Crossref PubMed Google Scholar, 23Obaya A.J. Mateyak M.K. Sedivy J.M. Oncogene. 1999; 18: 2934-2941Crossref PubMed Scopus (201) Google Scholar). c-Myc protein is stabilized after activation of several signal transduction pathways that inhibit glycogen synthase kinase-3β (GSK-3β), such as the Raf-MEK-ERK kinase cascade or the PI3K (phosphatidylinositol-3-OH kinase)-Akt pathway. The ERK and GSK-3β kinases phosphorylate two sites, Ser-62 and which are the of c-Myc and are in c-Myc M. A. Klein G. Luscher B. Oncogene. 1993; Google Scholar, B. Hann S.R. Mol. Cell. Biol. 1994; 14: PubMed Scopus Google Scholar, B.J. C. K. T. Evan G. Oncogene. 1994; Google Scholar, R. G. J. Mol. Cell. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). phosphorylation of c-Myc degradation through the R. G. J. Mol. Cell. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). In response to a transcription of the c-myc gene is increased and c-Myc protein is phosphorylated on the Ser-62 which results in at Ser-62 is also for the phosphorylation of c-Myc at by which is with c-Myc degradation M. A. Klein G. Luscher B. Oncogene. 1993; Google Scholar, B.J. C. K. T. Evan G. Oncogene. 1994; Google Scholar, R. G. J. Mol. Cell. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, B. Hann S.R. J. Cell. 1999; PubMed Scopus (23) Google Scholar). phosphorylation to degradation of c-Myc through the of to results in a and c-Myc protein M. A. Klein G. Luscher B. Oncogene. 1993; Google Scholar, B.J. C. K. T. Evan G. Oncogene. 1994; Google Scholar, R. G. J. Mol. Cell. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). Cyclin of the target of has been to as it to K. D. EMBO J. 1994; 13: PubMed Scopus Google Scholar, A. A. M. Oncogene. 1995; Google Scholar). However, recent that cyclin G1 be involved in that are not with Cyclin G1 is with cyclin-dependent kinase and which is also as cyclin kinase Y. I. M. H. FEBS Lett. 1997; PubMed Scopus Google Scholar, H. N. Y. H. 1997; PubMed Scopus Google Scholar). In addition, of overexpression in human cells, it has been that cyclin G1 as an protein Kim D. N. Kim J.M. I. J. Full Text Full Text PDF PubMed Scopus Google Scholar, M. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). cyclin G1 is also involved in G2/M phase arrest in response to DNA damage H. 2002; PubMed Scopus Google Scholar) and in the of K. C. Oncogene. 1999; 18: PubMed Scopus Google Scholar), that it has a these is of the of cyclin G1 when it is with or of the of In a study, we that cyclin G1 was in cancer that it regulated cyclin B1 at the transcriptional of In addition, in that study, cyclin G1 was to overcome radiation-induced G2 in increased M. S. Kim J. Cell 13: PubMed Scopus Google Scholar). In this study, we further the mechanisms of cyclin G1-mediated transcriptional activation of B1. Cyclin G1 with Cdk5, which in kinase activation of Cdk5 phosphorylated c-Myc on Ser-62, and the phosphorylated c-Myc directly to the E-box promoter region of cyclin B1, in increased cyclin B1 promoter was from for cyclin cyclin B1, c-Myc, ERK, and Cdk5 from and from and GSK-3β from c-Myc and Cdk5 protein from and overexpression of cyclin human cyclin G1 was into M. S. Kim J. Cell 13: PubMed Scopus Google Scholar, Res. 2002; PubMed Scopus Google Scholar). The cyclin B1 and provided by Engeland and by on the of c-Myc was into the after which in in the c-Myc sequence was by and Cell or human cell and cells in with and at in a in and at with to from a of at a of at the and with to the The cells a Cell for human cyclin cyclin B1, c-Myc, and was from transfected with these for cells transfected or Cell cell cycle cells in at for at the cells with and in of the of of and the for at and a In with cyclin G1 and Cdk5 after which the on protein and in kinase and c-Myc as G1 and also in the kinase on after which the by transfected with of expression and of with of CDE, CHR, and E-box and cyclin B1 expression The cells and activity was with the results to the expression results the of E-box was with and of was with the at for The was from the E-box on a The was and an was protein and cyclin cells in and for at for The cells with for the in after which of cell in and with c-Myc the on protein and on after which the by cells with in at for The was by on which chromatin of with Ser-62, or for The binding of c-Myc and to the cyclin B1 promoter was by a DNA and the DNA The as for by of at at and at by The was to to a was to the was by the level of during the early phase of the In and of the c-Myc protein was the by protein or by on with in by the for at the with The in and by the E-box-dependent of Cyclin B1 by Cyclin of the cyclin G1 to cancer cells increased cyclin B1 protein levels by However, of cyclin G1 this a study that overexpression of cyclin G1 cyclin B1 at the transcriptional level M. S. Kim J. Cell 13: PubMed Scopus Google Scholar), the by which cyclin G1 the transcription activity of cyclin B1 was Deletion or point mutations within the cyclin B1 promoter region revealed that increased cyclin B1 promoter activity in cells that cyclin G1 was by of of the E-box site in the cyclin B1 promoter which is the c-Myc binding site In addition, the level of promoter activity was to be to that of cells However, the of point or sites, which are the cell cycle-dependent transcriptional elements in the cyclin B1 not the transcriptional activity of cyclin B1 in cells that cyclin Furthermore, in cells that cyclin the transcription activity of cyclin B1 was by of and which are the activating elements in the cyclin B1 promoter Taken together, these results indicate that cyclin G1 overexpression the binding activity of c-Myc on the E-box of the cyclin B1 promoter of c-Myc in Cyclin G1-mediated of Cyclin G1 overexpression increased the expression of c-Myc, which is of the target that bind to the E-box Therefore, we c-Myc expression to it was to the cyclin G1-mediated transcriptional activation of cyclin B1. of cells that cyclin G1 with cyclin B1 protein levels as well as promoter that cyclin G1-mediated c-Myc expression was involved in the promoter activation of cyclin B1 by cyclin G1 and Furthermore, the increased DNA binding activity that was observed when an E-box was to cyclin cell was by with and when cells that been with a E-box the DNA binding activity of c-Myc by Cyclin level of c-Myc in cells that overexpress cyclin G1 not Therefore, we protein or the protein of c-Myc was by cyclin The of c-Myc with was increased by cyclin G1 overexpression when with that of cells However, when we c-Myc protein observed the and cyclin cells which that cyclin G1 c-Myc protein of c-Myc on Ser-62 by Cyclin c-Myc is regulated by the phosphorylation of and Ser-62 M. A. Klein G. Luscher B. Oncogene. 1993; Google Scholar, B.J. C. K. T. Evan G. Oncogene. 1994; Google Scholar, R. G. J. Mol. Cell. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, B. Hann S.R. J. Cell. 1999; PubMed Scopus (23) Google Scholar), the phosphorylation of c-Myc phosphorylation of c-Myc on both Ser-62 and was observed in cells that cyclin G1 the phosphorylation levels of c-Myc in the of c-Myc protein expression of on Ser-62 was to be increased by cyclin G1 however, was observed in the expression of on when and cyclin cells that cyclin G1 overexpression the c-Myc protein phosphorylation on Ser-62. The DNA binding activity observed when we used the E-box also that increased DNA binding activity to the E-box in cells that cyclin G1 was by the of to on however, this not when to on was that on Ser-62 was responsible for the increased DNA binding activity to the E-box of the cyclin B1 promoter in cells that cyclin directly the in binding activity of c-Myc to the cyclin B1 we chromatin and the E-box DNA in of cyclin cells for c-Myc and However, the of not bind to the cyclin B1 and when we a of the Moreover, a the of cells transfected with point revealed that of or on Ser-62 resulted in binding to the cyclin B1 promoter region that of on not with the point c-Myc on Ser-62 a not cyclin B1 protein expression or cyclin B1 promoter in the cyclin However, the cyclin B1 protein expression and promoter activity in the of Moreover, a of c-Myc on not cyclin G1-mediated cyclin B1 protein expression or promoter of to cyclin cells increased cyclin B1 protein expression and promoter however, this was not in the of that c-Myc phosphorylation on Ser-62 is important for increased cyclin B1 promoter activity by cyclin G1 was increased of or cells, these cells a which that phosphorylation of c-Myc on Ser-62 by cyclin G1 overexpression increased the protein of c-Myc, as well as the binding activity of the E-box region of the cyclin B1 However, the of c-Myc increased the protein of of Cdk5 by Cyclin G1 c-Myc on activity of Cdk5, a binding of cyclin was increased in cyclin cells In addition, of the cells with or G1 this kinase activity when c-Myc protein was used as a phosphorylation of c-Myc on Ser-62 and cyclin B1 protein expression in cyclin cells also by with or that Cdk5 is involved in cyclin G1-mediated c-Myc phosphorylation and cyclin B1 as well as in cyclin B1 transcriptional activity and cyclin G1 or Cdk5 directly regulated c-Myc an in kinase was with G1 protein not when c-Myc was used as a However, with protein c-Myc and with G1 and protein which that Cdk5 is responsible for c-Myc phosphorylation and of cyclin G1 and that Cdk5 this An in a also that Cdk5 directly to c-Myc and that cyclin G1 this binding Furthermore, of G1 protein to the cell of resulted in a expression of cyclin which in increased the level of c-Myc phosphorylation on Ser-62 activation of Cdk5 by cyclin cell that with protein c-Myc phosphorylation with G1 and with G1 and increased these Taken together, these results indicate that cyclin G1-mediated c-Myc phosphorylation on Ser-62 and cyclin B1 expression resulted from Cdk5 activation by cyclin of c-Myc in the with binding of c-Myc with Cdk5 was in the of cells with c-Myc we the binding activity of several of The was to bind to however, observed Cdk5 and and indicate that sequence of the of c-Myc is the binding site that with of of Cdk5 in Cyclin in M and Cell has been reported that cyclin G1 overexpression results in increased radiation-induced M phase arrest and cell In this study, activation of Cdk5 by cyclin G1 phosphorylated c-Myc on Ser-62, which was in responsible for increased cyclin B1 promoter Therefore, we Cdk5 to it was involved in M phase arrest and cell a mitosis was by and for a of in cells that cyclin G1 in However, when cells that cyclin G1 with this was G2/M phase arrest by in cells that cyclin G1 was also by increased the expression of cyclin G1 and c-Myc phosphorylation on Ser-62 and cyclin B1, as well as Cdk5 kinase However, of cyclin G1 or Cdk5 these Furthermore, increased cell death in response to in cells that cyclin G1 was also by Taken together, these results that an in cyclin M phase arrest and cell death was mediated by Cdk5 have a for cyclin which previously been to activation of cyclin B1 transcription M. S. Kim J. Cell 13: PubMed Scopus Google Scholar). have c-Myc phosphorylation on Ser-62 by Cdk5, which is a of cyclin we have demonstrated that c-Myc phosphorylation is essential for transcriptional activation of cyclin B1 by cyclin G1 to occur. Cyclin G1 was as a of the cyclin and is of the target of transcriptional factor K. D. EMBO J. 1994; 13: PubMed Scopus Google Scholar, A. A. M. Oncogene. 1995; Google Scholar). However, in the that cyclin G1 in transcriptional activation of cyclin B1 a In addition, the cyclin G1-mediated of cyclin B1 expression was observed in both and Moreover, are that can repress the transcription of cyclin B1 X.Y. Grove L. Datta N.S. Katula K. Long M.W. Prochownik E.V. Cancer Res. 2001; 61: 6487-6493PubMed Google Scholar), which that is not involved in cyclin B1 Cyclin G1 has been to an important in K. C. Oncogene. 1999; 18: PubMed Scopus Google Scholar, S. S. Oncogene. 1996; 13: Google Scholar, D. M. J. Biol. Chem. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar) including M. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar), and the that it with have been Y. I. M. H. FEBS Lett. 1997; PubMed Scopus Google Scholar, K. C. M. C. D. Mol. Cell. Biol. 1996; PubMed Scopus (88) Google Scholar). However, the of cyclin G1 are the subject of For transcription of cyclin G1 is within a of growth factor of cells M.L. R. A.J. Cell Res. 1997; PubMed Scopus Google Scholar). In addition, gene of cyclin G1 proliferation of human cells M. L. Cancer Res. 1995; Google Scholar), which that cyclin G1 a in cell growth that cyclin G1 has activity K. C. Oncogene. 1999; 18: PubMed Scopus Google Scholar, S. S. Oncogene. 1996; 13: Google Scholar, 1998; 28: PubMed Scopus Google Scholar). Furthermore, a recent study that a level of cyclin G1 results in a of activity and promote growth M. S. Kim J. Cell 13: PubMed Scopus Google Scholar), levels of cyclin G1 growth we that cyclin G1 radiation-induced M phase arrest and cell death as a of increased cyclin B1 promoter Synthesis of cyclin B1 during the cell cycle is regulated primarily at the transcriptional level M. S. Kim J. Cell 13: PubMed Scopus Google Scholar), and cell transcription by this promoter is regulated by a and tandem element (7Lange-zu Dohna C. Brandeis M. Berr F. Mossner J. Engeland K. FEBS Lett. 2000; 484: 77-81Crossref PubMed Scopus (48) Google Scholar). However, the cyclin B1 promoter is also subject to activation by we have demonstrated that cells that overexpress cyclin G1 increased the promoter activity of cyclin B1 through activation of the which that activation of the cyclin B1 promoter by cyclin G1 is on c-Myc in cyclin G1 overexpression increased the c-Myc protein level However, levels of c-Myc and c-Myc protein not by cyclin the protein of c-Myc was increased Therefore, we the phosphorylation of c-Myc to it was by cyclin It has been reported that phosphorylation and Ser-62 are with c-Myc degradation M. A. Klein G. Luscher B. Oncogene. 1993; Google Scholar, B. Hann S.R. Mol. Cell. Biol. 1994; 14: PubMed Scopus Google Scholar, B.J. C. K. T. Evan G. Oncogene. 1994; Google Scholar, R. G. J. Mol. Cell. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar), and in this study we observed that cyclin G1 increased c-Myc phosphorylation on Ser-62. However, increased phosphorylation of c-Myc on in cells that cyclin G1 was not the of overexpression of cyclin G1 of c-Myc on Ser-62 is regulated by and GSK-3β is involved in c-Myc phosphorylation on cyclin G1 overexpression not the of and GSK-3β phosphorylation we c-Myc phosphorylation by or the mechanism by which on increased by cyclin G1 is it is that increased on Ser-62 the of on when we the of the or of c-Myc on was to have In the of c-Myc on Ser-62 was to the binding activity of the cyclin B1 promoter It has been reported that c-Myc phosphorylation on Ser-62 and has on the transcriptional activity of M.L. Oncogene. 2001; PubMed Scopus Google Scholar, G.F. Hann S.R. Mol. Cell. Biol. 2000; PubMed Scopus Google Scholar, K. A.J. M. N. Mol. Cell. Biol. 2000; PubMed Scopus Google Scholar). However, several have that phosphorylation of c-Myc the transcriptional activity of target R. G. J. Mol. Cell. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, B. M. F. A. G. M. G. A. Mol. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar, A. Cancer Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). also that phosphorylation of c-Myc on Ser-62, not on ability to bind to the E-box of cyclin B1 It is not on Ser-62 the promoter activity of cyclin however, it has been that to be to the E-box site of promoter B. M. F. A. G. M. G. A. Mol. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar), which is to the results of this Cyclin G1 not have kinase we binding of cyclin such as Cdk5, to involved in c-Myc Cdk5 kinase activity was to be increased by cyclin G1 overexpression, and of Cdk5 by of c-Myc phosphorylation on Ser-62 as well as of cyclin B1 promoter In addition, an in kinase revealed that Cdk5 c-Myc phosphorylation and that with cyclin G1 this cyclin G1 not Furthermore, the results of this study revealed an c-Myc and Cdk5 which that this was important for the phosphorylation of c-Myc by Cdk5 to occur. previously reported that cyclin G1 was in cancer including M. S. Kim J. Cell 13: PubMed Scopus Google Scholar). In this study, the cyclin G1 levels in several cancer cell to be well with c-Myc phosphorylation on Ser-62, as well as with cyclin B1 both of which mediated by Cdk5 Taken together, these results that the cyclin B1 expression level in cyclin cancer cells was by It has been that cyclin G1 overexpression results in increased as a of the increased transition from the G2 to M which occurs to cyclin B1 promoter activation M. S. Kim J. Cell 13: PubMed Scopus Google Scholar). 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