Jumonji Regulates Cardiomyocyte Proliferation via Interaction with Retinoblastoma Protein

Abstract

Jumonji (JMJ) can function as a transcriptional repressor and plays critical roles in embryonic development including heart development in mice. Although JMJ has been suggested to play a role in cell growth, the molecular mechanisms have not been resolved. The present data demonstrate that JMJ interacts with the retinoblastoma protein (Rb), one of the master regulatory genes of cell cycle. JMJ potentiates the repression function of Rb on E2F activities, leading to reduced cell cycle progression. The transcriptional repression domain of JMJ is critical for the interaction with Rb as well as repression of cell cycle. The physiological relevance of the association between Rb and JMJ was assessed in cardiomyocytes. Primary cardiomyocytes cultured from homozygous jmj knock-out mouse embryos (jmj mutants) show increased cell mitosis in a cardiomyocyte-specific manner. Reporter gene analyses demonstrate that promoter activities of cyclin D1, cyclin D2, and Cdc2 are up-regulated in jmj mutant cardiomyocytes. These data suggest that JMJ down-regulates the cell growth via interaction with Rb, which would provide important insights into the cardiac defects observed in jmj mutant mice. Jumonji (JMJ) can function as a transcriptional repressor and plays critical roles in embryonic development including heart development in mice. Although JMJ has been suggested to play a role in cell growth, the molecular mechanisms have not been resolved. The present data demonstrate that JMJ interacts with the retinoblastoma protein (Rb), one of the master regulatory genes of cell cycle. JMJ potentiates the repression function of Rb on E2F activities, leading to reduced cell cycle progression. The transcriptional repression domain of JMJ is critical for the interaction with Rb as well as repression of cell cycle. The physiological relevance of the association between Rb and JMJ was assessed in cardiomyocytes. Primary cardiomyocytes cultured from homozygous jmj knock-out mouse embryos (jmj mutants) show increased cell mitosis in a cardiomyocyte-specific manner. Reporter gene analyses demonstrate that promoter activities of cyclin D1, cyclin D2, and Cdc2 are up-regulated in jmj mutant cardiomyocytes. These data suggest that JMJ down-regulates the cell growth via interaction with Rb, which would provide important insights into the cardiac defects observed in jmj mutant mice. Jumonji (jmj) 1The abbreviations used are: JMJ or jmj, Jumonji; Rb, retinoblastoma protein; RBP, Rb-binding protein; Cdk, cyclin-dependent kinase; HDAC, histone deacetylase; E, embryonic day; TR, transcriptional repression; GST, glutathione S-transferase; CM, cardiomyocyte; GFP, green fluorescent protein; aa, amino acid(s); DMEM, Dulbecco's modified Eagle's medium; FBS, fetal bovine serum; X-gal, 5-bromo-4-chloro-3-indolyl-β-d-galactopyranoside; PBS, phosphate-buffered saline; PBST, 0.2% Triton X-100 in PBS; P-H3, phosphohistone H3; BrdUrd, bromodeoxyuridine; pRb, hyperphosphorylated Rb; J-Wt, wild type JMJ; J-Nt, N-terminal JMJ. plays important roles in mouse embryonic development including cardiovascular development, which was first identified by gene trap technologies (1Takeuchi T. Yamazaki Y. Katoh-Fukui Y. Tsuchiya R. Kondo S. Motoyama J. Higashinakagawa T. Genes Dev. 1995; 9: 1211-1222Crossref PubMed Scopus (257) Google Scholar, 2Lee Y. Song A.J. Baker R. Micales B. Conway S.J. Lyons G.E. Circ. Res. 2000; 86: 932-938Crossref PubMed Scopus (124) Google Scholar). Homozygous jmj knock-out mice (hereafter referred to as jmj mutants) displayed severe cardiac morphological defects and altered heart-specific gene expression (for review, see Ref. 3Jung J. Mysliwiec M.R. Lee Y. Dev. Dyn. 2005; 232: 21-32Crossref PubMed Scopus (60) Google Scholar). The jumonji protein (JMJ) is a member of the JMJ transcription factor family and belongs to an AT-rich interaction domain transcriptional factor family (4Gregory S.L. Kortschak R.D. Kalionis B. Saint R. Mol. Cell. Biol. 1996; 16: 792-799Crossref PubMed Scopus (136) Google Scholar, 5Herrscher R.F. Kaplan M.H. Lelsz D.L. Das C. Scheuermann R. Tucker P.W. Genes Dev. 1995; 9: 3067-3082Crossref PubMed Scopus (231) Google Scholar, 6Kortschak R.D. Tucker P.W. Saint R. Trends Biochem. Sci. 2000; 25: 294-299Abstract Full Text Full Text PDF PubMed Scopus (148) Google Scholar). In vitro analyses on structural and functional relationships revealed that JMJ contains distinct functional domains for transcriptional repression, DNA binding, and nuclear localization (7Kim T.G. Kraus J.C. Chen J. Lee Y. J. Biol. Chem. 2003; 278: 42247-42255Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar). More recently, it has been reported that JMJ represses the expression of cardiac-specific genes such as the atrial natriuretic factor gene through inhibiting Nkx2.5 and GATA4 activities that are important cardiac-restricted transcription factors (8Kim T.G. Chen J. Sadoshima J. Lee Y. Mol. Cell. Biol. 2004; 24: 10151-10160Crossref PubMed Scopus (74) Google Scholar). Therefore, it is possible that JMJ employs multiple regulatory mechanisms to regulate the target gene expression. Although the molecular basis of JMJ for transcriptional regulation in the heart is now emerging, the evidence underlying the causes of the cardiac defects observed in jmj mutants is still lacking. JMJ contains the AT-rich interaction domain and jmj-like domain (jmjN/jmjC) that constitutes a jmj family of transcription factors (9Balciunas D. Ronne H. Trends Biochem. Sci. 2000; 25: 274-276Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar, 10Clissold P.M. Ponting C.P. Trends Biochem. Sci. 2001; 26: 7-9Abstract Full Text Full Text PDF PubMed Scopus (199) Google Scholar). Interestingly, these domains are also conserved in retinoblastoma protein (Rb)-binding protein 1 (RBP1) and RBP2, which were originally identified as Rb pocket domain-binding proteins (11Defeo-Jones D. Huang P.S. Jones R.E. Haskell K.M. Vuocolo G.A. Hanobik M.G. Huber H.E. Oliff A. Nature. 1991; 352: 251-254Crossref PubMed Scopus (253) Google Scholar, 12Fattaey A.R. Helin K. Dembski M.S. Dyson N. Harlow E. Vuocolo G.A. Hanobik M.G. Haskell K.M. Oliff A. Defeo-Jones D. Jones R.E. Oncogene. 1993; 8: 3149-3156PubMed Google Scholar). Rb is known as a key regulator on cell cycle progression and differentiation partly via suppressing E2F activity (13Weinberg R.A. Cell. 1995; 81: 323-330Abstract Full Text PDF PubMed Scopus (4326) Google Scholar, 14Frolov M.V. Dyson N.J. J. Cell Sci. 2004; 117: 2173-2181Crossref PubMed Scopus (334) Google Scholar, 15Ikeda M.A. Jakoi L. Nevins J.R. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 3215-3220Crossref PubMed Scopus (225) Google Scholar), suggesting the role of JMJ in the regulation of cell proliferation. The inhibition of E2F activity leads to failure of activation of numerous genes required for S-phase entry or DNA synthesis including c-myc, and J.C. Mol. Cell. Biol. 9: PubMed Scopus Google Scholar, R.A. Mol. Cell. Biol. PubMed Scopus Google Scholar, Nevins J.R. Nature. 1993; PubMed Scopus Google Scholar). In E2F activity is by association with In to Rb is multiple by which E2F from Rb, cell cycle progression into and Rb and such as and are known to with through the conserved pocket domain such as N. C. Harlow E. J. PubMed Google Scholar), histone 1 and A. A.J. T. Nature. PubMed Scopus Google Scholar, Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). observed in jmj partly to J. Mysliwiec M.R. Lee Y. Dev. Dyn. 2005; 232: 21-32Crossref PubMed Scopus (60) Google Scholar), the role of JMJ in cell has been also suggested by jmj mutant mice with a and cardiac defects such as and embryonic Y. Song A.J. Baker R. Micales B. Conway S.J. Lyons G.E. Circ. Res. 2000; 86: 932-938Crossref PubMed Scopus (124) Google Scholar). These cardiovascular defects cardiovascular H. J. 2004; PubMed Google Scholar, D. Circ. Res. 2000; 86: PubMed Scopus Google Scholar). In to the Y. Song A.J. Baker R. Micales B. Conway S.J. Lyons G.E. Circ. Res. 2000; 86: 932-938Crossref PubMed Scopus (124) Google Scholar), jmj mutant embryos with a cell growth in the and J. K. Kondo S. T. Dev. PubMed Scopus Google Scholar), suggesting the role of JMJ in cell proliferation. In jmj mutant mice with a embryonic which and increased cyclin expression in the of the T. K. Kondo S. Dev. 86: PubMed Scopus Google Scholar, H. K. R. Y. T. Dev. Cell. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). The molecular by which JMJ represses the cyclin promoter activity in the of the heart on the of cell cell cell and heart is and In mouse embryos to and is into an and of the the and the and to a to cardiomyocytes leading to the of the Therefore, the is of the of cardiomyocytes. the by from the cell cycle In to cell cycle numerous transcription factors have been suggested to play a role in that knock-out mice a including cell and N. S. N. Google Scholar, Dyson E. J. Genes Dev. 8: PubMed Scopus Google Scholar, L. C. M.A. 1995; PubMed Google Scholar, J. Google Scholar, S. Y. Cell. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). on these that JMJ to Rb to the Rb which to altered cell as a demonstrate that JMJ the function of Rb on E2F activities, which is by interaction between the transcriptional repression domain of JMJ and the pocket domain of The of JMJ in up-regulated cell of cardiomyocytes from jmj to up-regulated promoter activities of cyclin D1, cyclin D2, and which to of These suggest that JMJ of the via interaction with Rb, which to a of jmj mutant expression in the wild type JMJ and mutants were into the as (7Kim T.G. Kraus J.C. Chen J. Lee Y. J. Biol. Chem. 2003; 278: 42247-42255Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar). glutathione the expression JMJ and mutants were the and the proteins were from or as (7Kim T.G. Kraus J.C. Chen J. Lee Y. J. Biol. Chem. 2003; 278: 42247-42255Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar). The JMJ wild type and the mutant amino were the The expression for Rb was by R. of S. L. C. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar), and mouse Rb S. B. Cell. 1993; Full Text PDF PubMed Scopus Google was used for in vitro The expression for Rb mutants and to were from D. and were from of Oncogene. Google Scholar). cyclin to and cyclin to promoter were into the The contains the promoter J. J. Biol. Chem. 2003; 278: Full Text Full Text PDF PubMed Scopus Google Scholar). Primary of of mouse embryonic was as with (8Kim T.G. Chen J. Sadoshima J. Lee Y. Mol. Cell. Biol. 2004; 24: 10151-10160Crossref PubMed Scopus (74) Google Scholar, B. T. H. Dev. Biol. PubMed Scopus Google Scholar). The were in and for and by the of the cell was and in with fetal bovine The the was by with and and in cultured were to a by cardiac jmj knock-out mice in a were to homozygous jmj knock-out which were by DNA as Y. Song A.J. Baker R. Micales B. Conway S.J. Lyons G.E. Circ. Res. 2000; 86: 932-938Crossref PubMed Scopus (124) Google Scholar). were by and with X-gal, in by were by and to Rb, D1, D2, and E, and embryonic and were in with and Cell by cardiomyocytes or were with for as were with for by with 0.2% Triton X-100 in for were with for 1 with with PBST, and by in were with and cardiac in for 1 were with by for 1 with and in were with 1 and an of was and were by the of by cardiac and were with a for phosphohistone embryonic were by in for and in were in and The were with and with and that with PBS, were with and and by the of the embryonic in were on of embryos to Reporter the promoter activities in the or of cardiomyocytes on were with of cyclin D1, cyclin D2, or promoter and of on a of were with of gene with of and with with of JMJ. the of JMJ on the repression activity of Rb on on a of were with of of of Rb, and of JMJ mutants by of the was with of the and of the a activities were and to The expression of proteins were by to E2F Rb, and JMJ. with Rb or and JMJ or were in a 1 1 and The cell were by with protein for 1 by with or a protein was and for 1 with the were to by with as in the Y. Song A.J. Baker R. Micales B. Conway S.J. Lyons G.E. Circ. Res. 2000; 86: 932-938Crossref PubMed Scopus (124) Google and JMJ wild type and mutants were in vitro by the promoter to mutants were by of mouse with and by in vitro by the or proteins to were with or in 1 for and with were to by or with or was used for data with a of In of Rb with amino that the JMJ contains domains that are conserved in transcription the and AT-rich interaction domains in R.D. Tucker P.W. Saint R. Trends Biochem. Sci. 2000; 25: 294-299Abstract Full Text Full Text PDF PubMed Scopus (148) Google Scholar, 10Clissold P.M. Ponting C.P. Trends Biochem. Sci. 2001; 26: 7-9Abstract Full Text Full Text PDF PubMed Scopus (199) Google Scholar). Interestingly, of JMJ is to and that with Rb, a master regulator of cell cycle (11Defeo-Jones D. Huang P.S. Jones R.E. Haskell K.M. Vuocolo G.A. Hanobik M.G. Huber H.E. Oliff A. Nature. 1991; 352: 251-254Crossref PubMed Scopus (253) Google Scholar, 12Fattaey A.R. Helin K. Dembski M.S. Dyson N. Harlow E. Vuocolo G.A. Hanobik M.G. Haskell K.M. Oliff A. Defeo-Jones D. Jones R.E. Oncogene. 1993; 8: 3149-3156PubMed Google Scholar). JMJ has been suggested to in cell cycle regulation Y. Song A.J. Baker R. Micales B. Conway S.J. Lyons G.E. Circ. Res. 2000; 86: 932-938Crossref PubMed Scopus (124) Google Scholar, T. K. Kondo S. Dev. 86: PubMed Scopus Google Scholar, H. K. R. Y. T. Dev. Cell. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar), JMJ with Rb in by JMJ was with Rb or Rb into were by analyses as 1 and Cell were with by analyses and The JMJ was with and were with by with or JMJ was were with Rb and the protein interaction in were The Rb or JMJ was cell with JMJ or with were to analyses as 1 and The Rb was cell and were with by or as the Rb was not cell JMJ and were with by or interaction of JMJ with These data demonstrate that JMJ interacts with Rb in are interacts with Rb in was with JMJ and Rb or of JMJ or Rb was by 1 and The of was cell Cell were with by as and the were cell and or JMJ Cell were by by and The of JMJ on E2F Rb is known to the cell cycle by it is possible that the association of Rb and JMJ the activity of the Rb activity on E2F is in the of the gene the promoter to a gene E2F the gene and of Rb with E2F activation by as the wild type JMJ was with Rb and JMJ activity by suggesting that JMJ potentiates the repression activity of Rb on the JMJ domain that repression JMJ mutants were with E2F and The N-terminal JMJ the domain repression to JMJ repression The mutant the domain also repression the domain mutant repression activity The proteins were including Rb and JMJ not These data that the domain of JMJ is and to the repression function of JMJ. The repression function of JMJ on the activation was on Rb, of the JMJ to E2F activity in the of These suggest that JMJ activation via the repression function of The between the of JMJ and the of that the domain of JMJ is critical for the repression function of Rb on E2F the protein interaction between the domain of JMJ and Rb the function of JMJ on Rb interaction of Rb with proteins and Rb one pocket domain of Rb or of and Y. Trends Biochem. Sci. Full Text PDF PubMed Scopus Google Scholar). the protein interaction of Rb that with the domain of mutants and mutants of were in with Rb and the suggesting that the pocket domain is not required for to JMJ. interaction with In in which the pocket domain was activity to suggesting that the pocket domain is for interaction with JMJ. The are in The wild type with wild type and mutants in a to not were by in vitro and protein to used that contains the pocket the pocket domain to required for to JMJ and The expression of and the domain is in the and with not with the interaction between JMJ and the interaction mutants of JMJ were to not and the are in that the domain of JMJ with Rb in These data that the pocket domain of Rb interacts with the domain of JMJ in JMJ also with of the pocket domain family such as and in vitro not suggesting that JMJ have a regulatory on the pocket domain between JMJ and Rb were by cell from cultured cardiomyocytes and cell with JMJ the JMJ that was in cell by the JMJ from embryos were to the JMJ protein was not the were with the JMJ was not with interaction between JMJ in cardiomyocytes and the pocket domain of The were The Rb proteins were as that the hyperphosphorylated Rb and the Rb in from and by analyses 1 and and were with the Rb was in embryonic not with and is that the of Rb to JMJ. that the of Rb to increased in cardiomyocytes from with which the cell cycle as the heart with the in 1 and these data demonstrate that JMJ and Rb with which the regulation of the Rb function on cell cycle progression. of Cell by to the repression activity of JMJ on E2F activities via interaction with Rb in the regulation of cell proliferation. The cardiomyocytes in the heart are to growth including from the and Genes Dev. 2003; PubMed Scopus Google Scholar). Therefore, the which the multiple growth from cell of the heart or from the Primary cardiomyocytes cultured from jmj mutants with a which severe cardiac defects and were used Y. Song A.J. Baker R. Micales B. Conway S.J. Lyons G.E. Circ. Res. 2000; 86: 932-938Crossref PubMed Scopus (124) Google Scholar). cell mitosis is in jmj cardiomyocytes cultured from embryonic The cardiomyocytes on were with by and cardiac The of cardiomyocytes was Interestingly, jmj mutant cardiomyocytes a in with wild that cell growth is up-regulated in mutants cell of cardiac was also in jmj assessed the cell of cardiac The that was not by cardiac was as cardiac cell such as and as a in cell were not altered in cardiac cultured from mutant as with wild Therefore, cell of not cardiac was up-regulated in jmj mutant were Although it has been that jmj is in the mouse the of that jmj have not been in the the expression of jmj in cultured on from jmj mutant mutant a the jmj which expression of jmj Y. Song A.J. Baker R. Micales B. Conway S.J. Lyons G.E. Circ. Res. 2000; 86: 932-938Crossref PubMed Scopus (124) Google Scholar). in was observed in a that was by cardiac not observed in cardiac These that jmj is a in cardiomyocytes cardiac Therefore, the increased of jmj mutant not to the that jmj not to in the in cell in jmj mutant cardiomyocytes an role of JMJ on cell proliferation. The of JMJ on Cell cycle progression is by to and are by activation of including and and which are by such as and These the of Rb that is required for cell cycle jmj mutants the regulation of cell growth, it is that cell cycle is by the of JMJ. the expression of critical of cell cycle are in the of gene of cell cycle in cardiomyocytes gene was into cardiomyocytes from embryonic the promoter activities of cyclin D1, cyclin D2, and Cdc2 in mutant cardiomyocytes were increased by and with of wild in promoter activities were observed with the or promoter These data suggest a possible role of JMJ in cyclin D1, cyclin D2, and Cdc2 promoter activities, which to inhibition of cell cycle progression. the expression of cell cycle proteins were in analyses were In with the from gene cardiomyocytes from mutant displayed increased protein of and In the protein of cyclin cyclin E, and in mutant cardiomyocytes were not altered with wild type The mutant of the hyperphosphorylated Rb the Rb, which is well with the increased promoter activities, leading to an expression of cyclin protein in mutant cardiomyocytes. These suggest that the increased promoter activities of cyclin D1, cyclin D2, and Cdc2 in jmj mutant cardiomyocytes in of Rb to the hyperphosphorylated Rb, which in cell cycle progression or cell cycle the repression function of JMJ on these the promoter activities of the cell cycle JMJ was in with the promoter activities of and were reduced by and with the activity of the gene The promoter activities of Cdc2 and not to by the promoter was also by JMJ. with the data in these that JMJ represses promoter activities of and and Cdc2 not repression activities of JMJ on cyclin expression to the cell the was with or reduced by with a repression activity as J-Wt, suggesting that the the domain is to cell cycle progression. These that the cyclin D1, cyclin D2, and Cdc2 are by which to the cell in wild type embryonic cardiomyocytes. would to the molecular mechanisms by which JMJ these The of JMJ on in that JMJ is in the of embryonic cardiomyocytes with a were in the jmj mutant heart with a in the and embryonic Y. Song A.J. Baker R. Micales B. Conway S.J. Lyons G.E. Circ. Res. 2000; 86: 932-938Crossref PubMed Scopus (124) Google Scholar). the cell in jmj mutant has not been in embryonic Therefore, activities of the of the jmj mutant with a between and these mutants are heart was with phosphohistone that and to cardiomyocytes Interestingly, cardiomyocytes were increased by in the of mutant well with data the increased cyclin promoter activities, and hyperphosphorylated Rb in cultured mutant cardiomyocytes and and In were observed in the mutant with wild type In were to increased was for in the mutant the in the mutant heart not to with wild type not Therefore, it is that JMJ as a regulatory factor of in a in a and manner. that the increased of jmj mutant cardiomyocytes in and the increased cell in the of of the of that cardiomyocytes from constitutes cardiomyocytes. the first evidence for a role of JMJ in the regulation of in an The interaction of JMJ with Rb in the function of Rb on E2F activities, leading to the of cell proliferation. The increased activities of the cyclin D1, cyclin D2, and Cdc2 in cultured jmj mutant cardiomyocytes of the hyperphosphorylated of Rb, which in to an in cell in the of JMJ. Therefore, present data the role of JMJ in suppressing cell in cardiomyocytes. These are by the increased cell of the cardiomyocytes in jmj mutant with a embryonic and the reported with a embryonic T. K. Kondo S. Dev. 86: PubMed Scopus Google Scholar, H. K. R. Y. T. Dev. Cell. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). is that of Rb to with data that JMJ with the of to a of Rb-binding proteins that are in the regulation of cell cycle such as and Huang Lee E. Cell. Full Text PDF PubMed Scopus Google Scholar, K. P.M. Google Scholar, S. Nevins J.R. Cell. 1991; Full Text PDF PubMed Scopus Google Scholar, A. Y. A. Nature. 2000; PubMed Scopus Google Scholar). These the physiological role of JMJ in cell via interaction with Rb in the on these In Rb is which can with E2F to In the of JMJ is to the Rb to the repression function of Rb on E2F activities, by or by inhibiting of Rb, the molecular basis to In Rb is by leading to the of association with S-phase genes to In to to Rb, JMJ down-regulates transcriptional activities of and the of hyperphosphorylated Rb as a of cell Rb contains the pocket domains that are conserved from to proteins have been identified to with Rb including cyclin D1, and such as and M.V. Dyson N.J. J. Cell Sci. 2004; 117: 2173-2181Crossref PubMed Scopus (334) Google Scholar, H. J. Cell. 1993; Full Text PDF PubMed Scopus Google Scholar, S. K. J. Cell. Full Text PDF PubMed Scopus Google Scholar, Mol. Cell. Biol. 1996; 16: PubMed Scopus (225) Google Scholar, L. R. S. D. A. Nature. PubMed Scopus Google Scholar). These proteins a conserved or that to the pocket domain of Rb with and the function of Rb A. M.R. Mol. Cell. Biol. 2000; PubMed Scopus Google Scholar). in vitro demonstrate that the Rb in JMJ is in the domain and that interaction the pocket domain of of the domain revealed that it not suggesting a of JMJ to Although the is well as a to the pocket domain and important for the function of Rb, are known Rb-binding proteins Y. Trends Biochem. Sci. Full Text PDF PubMed Scopus Google Scholar). an Rb is in and A. M.R. Mol. Cell. Biol. 2000; PubMed Scopus Google Scholar, Res. PubMed Scopus Google Scholar, Mol. Cell. Biol. 2000; PubMed Scopus Google Scholar, G.A. D. A. Mol. Cell. Biol. 2003; PubMed Scopus Google Scholar). The present data that the domain of JMJ to the pocket domain of Rb and is also critical for the Rb The functional of the domain is by the that domain was for transcriptional repression the underlying (7Kim T.G. Kraus J.C. Chen J. Lee Y. J. Biol. Chem. 2003; 278: 42247-42255Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar). has been reported embryonic and cardiomyocytes of the pocket domain family for S. N. E. J. Mol. Cell Full Text PDF PubMed Scopus Google Scholar). Therefore, it would to JMJ has for these proteins embryonic and regulate the cell cycle progression in to are the for by provide evidence that increased activities of cyclin D1, cyclin D2, and Cdc2 of cell growth partly by the of hyperphosphorylated Rb in cultured jmj mutant cardiomyocytes with a These data well with the up-regulated mitosis in the by phosphohistone of jmj mutant heart In cell mitosis in the not to show between wild and the mutant mice with a the Y. Song A.J. Baker R. Micales B. Conway S.J. Lyons G.E. Circ. Res. 2000; 86: 932-938Crossref PubMed Scopus (124) Google Scholar), suggesting cell growth in the the in the of mutant was not by defects in a role of the factors in cardiac proliferation. are that cell from the to is or that cycle is in the in increased cell in the and in jmj The molecular underlying of the in jmj mutants to have suggested that of between the and to J. J. Biol. Chem. 2003; 278: Full Text Full Text PDF PubMed Scopus Google Scholar, Dev. PubMed Scopus Google Scholar). cell or displayed to the Dyson E. J. Genes Dev. 8: PubMed Scopus Google Scholar, L. C. M.A. 1995; PubMed Google Scholar, S. Y. Cell. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, J. PubMed Google Scholar, H. 1995; PubMed Google Scholar). factors from and have been identified such as and D. H. C. R. Nature. 1995; PubMed Scopus Google Scholar, H. Chen H. B. C. Nature. 1995; PubMed Scopus Google Scholar, S. Dev. Biol. 2003; PubMed Scopus Google Scholar). Therefore, the of the of and defects on development in jmj Although the present that JMJ plays a regulatory role in via interaction with Rb, the of defects in jmj mutant embryos multiple roles of JMJ in cell cycle regulation or in target gene regulation in a and manner. The that JMJ contains the domain that is conserved in proteins P.M. Ponting C.P. Trends Biochem. Sci. 2001; 26: 7-9Abstract Full Text Full Text PDF PubMed Scopus (199) Google a possible role of JMJ in which to the of multiple target gene expression. The was from of and for and Mysliwiec for critical of the