Ikaros and Notch1, two regulators of gene transcription, are critically important at many stages of T cell development. Deregulation of Ikaros and Notch activities cooperate to promote T cell leukemogenesis, providing evidence that they function in converging pathways in developing T cells. In this report, a mechanism for Ikaros:Notch cooperativity is described, revealing a non-redundant role for Ikaros in regulating expression of the Notch target gene Hes1 in a leukemia T cell line. We provide evidence that Ikaros directly represses Hes1 in concert with the transcriptional repressor, RBP-Jκ, allowing for cross-talk between Notch and Ikaros that impacts regulation of CD4 expression. Taken together, these data describe a potential mechanism for Ikaros' function during T cell development and define Ikaros as an obligate repressor of Hes1. Ikaros and Notch1, two regulators of gene transcription, are critically important at many stages of T cell development. Deregulation of Ikaros and Notch activities cooperate to promote T cell leukemogenesis, providing evidence that they function in converging pathways in developing T cells. In this report, a mechanism for Ikaros:Notch cooperativity is described, revealing a non-redundant role for Ikaros in regulating expression of the Notch target gene Hes1 in a leukemia T cell line. We provide evidence that Ikaros directly represses Hes1 in concert with the transcriptional repressor, RBP-Jκ, allowing for cross-talk between Notch and Ikaros that impacts regulation of CD4 expression. Taken together, these data describe a potential mechanism for Ikaros' function during T cell development and define Ikaros as an obligate repressor of Hes1. Ikaros is a nuclear protein whose function is essential for normal T cell development (1Georgopoulos K. Winandy S. Avitahl N. Annu. Rev. Immunol. 1997; 15: 155-176Crossref PubMed Scopus (213) Google Scholar, 2Winandy S. Wu L. Wang J.H. Georgopoulos K. J. Exp. Med. 1999; 190: 1039-1048Crossref PubMed Scopus (135) Google Scholar, 3Urban J.A. Winandy S. J. Immunol. 2004; 173: 4470-4478Crossref PubMed Scopus (36) Google Scholar). Ikaros also functions as a tumor suppressor in the T cell lineage as evidenced by the 100% penetrance of T cell leukemogenesis observed in genetically engineered Ikaros-deficient mice (4Winandy S. Wu P. Georgopoulos K. Cell. 1995; 83: 289-299Abstract Full Text PDF PubMed Scopus (367) Google Scholar, 5Wang J.H. Nichogiannopoulou A. Wu L. Sun L. Sharpe A.H. Bigby M. Georgopoulos K. Immunity. 1996; 5: 537-549Abstract Full Text PDF PubMed Scopus (512) Google Scholar, 6Kathrein K.L. Lorenz R. Minniti Innes A. Griffiths E. Winandy S. Mol. Cell. Biol. 2005; 25: 1645-1654Crossref PubMed Scopus (53) Google Scholar). The Notch receptor is also essential for T cell development and its constitutive activation also leads to T leukemogenesis in mice (7Radtke F. Wilson A. Stark G. Bauer M. van Meerwijk J. MacDonald H.R. Aguet M. Immunity. 1999; 10: 547-558Abstract Full Text Full Text PDF PubMed Scopus (1176) Google Scholar, 8Pui J.C. Allman D. Xu L. DeRocco S. Karnell F.G. Bakkour S. Lee J.Y. Kadesch T. Hardy R.R. Aster J.C. Pear W.S. Immunity. 1999; 11: 299-308Abstract Full Text Full Text PDF PubMed Scopus (807) Google Scholar, 9Aster J.C. Pear W.S. Curr. Opin. Hematol. 2001; 8: 237-244Crossref PubMed Scopus (67) Google Scholar). Interestingly, deregulation of Ikaros and Notch pathways cooperate in leukemogenesis in both mouse and humans (10Dumortier A. Jeannet R. Kirstetter P. Kleinmann E. Sellars M. dos Santos N.R. Thibault C. Barths J. Ghysdael J. Punt J.A. Kastner P. Chan S. Mol. Cell. Biol. 2006; 26: 209-220Crossref PubMed Scopus (134) Google Scholar, 11Beverly L.J. Capobianco A.J. Cancer Cell. 2003; 3: 551-564Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar, 12Beverly L.J. Capobianco A.J. Trends Mol. Med. 2004; 10: 591-598Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar, 13Lopez-Nieva P. Santos J. Fernandez-Piqueras J. Carcinogenesis. 2004; 25: 1299-1304Crossref PubMed Scopus (36) Google Scholar). However, the mechanism of cooperative function of Ikaros and Notch, which likely also contributes to the normal developmental process, is unknown. The Notch receptor is a transmembrane protein that undergoes two proteolytic cleavage events upon recognition of its extracellular ligand (members of the Delta or Serrate/Jagged family) (14Schweisguth F. Curr. Biol. 2004; 14: R129-R138Abstract Full Text Full Text PDF PubMed Google Scholar). These cleavages free the intracellular domain, which travels to the nucleus. In the nucleus, intracellular Notch regulates transcription of Notch target genes through its binding to and activation of the transcriptional repressor CSL (designated RBP-Jκ/CBF-1 in mammals). Ikaros and RBP-Jκ (RBP-J) are able to bind to the same DNA sequences in electrophoretic mobility shift assays, and it has been suggested that they may compete for binding (10Dumortier A. Jeannet R. Kirstetter P. Kleinmann E. Sellars M. dos Santos N.R. Thibault C. Barths J. Ghysdael J. Punt J.A. Kastner P. Chan S. Mol. Cell. Biol. 2006; 26: 209-220Crossref PubMed Scopus (134) Google Scholar). The mammalian Notch family consists of four receptors, Notch1, -2, -3, and -4 (15Baron M. Semin. Cell Dev. Biol. 2003; 14: 113-119Crossref PubMed Scopus (276) Google Scholar). Although thymocytes express Notch1, -2, and -3 (16Felli M.P. Maroder M. Mitsiadis T.A. Campese A.F. Bellavia D. Vacca A. Mann R.S. Frati L. Lendahl U. Gulino A. Screpanti I. Int. Immunol. 1999; 11: 1017-1025Crossref PubMed Scopus (164) Google Scholar), a non-redundant essential role in T cell development has only been established for Notch1 (7Radtke F. Wilson A. Stark G. Bauer M. van Meerwijk J. MacDonald H.R. Aguet M. Immunity. 1999; 10: 547-558Abstract Full Text Full Text PDF PubMed Scopus (1176) Google Scholar). However, constitutively active forms of Notch1, Notch2, or Notch3 expressed as a transgene in mouse bone marrow can lead to T cell leukemogenesis (9Aster J.C. Pear W.S. Curr. Opin. Hematol. 2001; 8: 237-244Crossref PubMed Scopus (67) Google Scholar). This suggests that whereas Notch1 may be the critical Notch receptor for T cell development, deregulation of any Notch is sufficient to induce leukemogenesis. Leukemogenesis induced by constitutively active Notch is similar in phenotype to that induced by Ikaros deficiency, suggesting that Ikaros and Notch lie in a linear pathway during T cell development. In both cases, leukemia is specific for the T cell lineage, arises within thymocyte population, and requires pre-TCR or TCR signaling (2Winandy S. Wu L. Wang J.H. Georgopoulos K. J. Exp. Med. 1999; 190: 1039-1048Crossref PubMed Scopus (135) Google Scholar, 5Wang J.H. Nichogiannopoulou A. Wu L. Sun L. Sharpe A.H. Bigby M. Georgopoulos K. Immunity. 1996; 5: 537-549Abstract Full Text PDF PubMed Scopus (512) Google Scholar, 17Zweidler-McKay P.A. Pear W.S. Semin. Cancer Biol. 2004; 14: 329-340Crossref PubMed Scopus (43) Google Scholar). Despite the importance of Notch1 in leukemogenesis and T cell development, only a handful of direct Notch target genes have been identified in developing T cells (18Reizis B. Leder P. Genes Dev. 2002; 16: 295-300Crossref PubMed Scopus (174) Google Scholar, 19Anderson A.C. Robey E.A. Huang Y.H. Curr. Opin. Genet. Dev. 2001; 11: 554-560Crossref PubMed Scopus (48) Google Scholar). One of the first described target genes for Notch-induced transcriptional activation was the gene encoding the transcriptional repressor, Hairy Enhancer of Split-1 (Hes1) (20Jarriault S. Brou C. Logeat F. Schroeter E.H. Kopan R. Israel A. Nature. 1995; 377: 355-358Crossref PubMed Scopus (1223) Google Scholar). Hes1, like Notch1, is essential for T cell development (21Tomita K. Hattori M. Nakamura E. Nakanishi S. Minato N. Kageyama R. Genes Dev. 1999; 13: 1203-1210Crossref PubMed Scopus (182) Google Scholar). Although most Hes1 gene targets that are important in regulation of T cell development are unknown, two potential targets have been defined. CD4 was the first identified target for Hes1 repressive activity in T cells (22Kim H.K. Siu G. Mol. Cell. Biol. 1998; 18: 7166-7175Crossref PubMed Scopus (78) Google Scholar, 23Allen III, R.D. Kim H.K. Sarafova S.D. Siu G. Mol. Cell. Biol. 2001; 21: 3071-3082Crossref PubMed Scopus (51) Google Scholar). The cell cycle-dependent kinase inhibitor gene p27kip1 also has been identified as a potential Hes1 target (24Murata K. Hattori M. Hirai N. Shinozuka Y. Hirata H. Kageyama R. Sakai T. Minato N. Mol. Cell. Biol. 2005; 25: 4262-4271Crossref PubMed Scopus (177) Google Scholar). Interestingly, CD4 and p27kip1 are also potential Ikaros target genes because their expression is up-regulated upon re-introduction of Ikaros into the JE131 Ikaros null T leukemia cell line (6Kathrein K.L. Lorenz R. Minniti Innes A. Griffiths E. Winandy S. Mol. Cell. Biol. 2005; 25: 1645-1654Crossref PubMed Scopus (53) Google Scholar). Because of this potential connection, we began to investigate the role of Ikaros in regulation of Hes1. In this report, we demonstrate that Ikaros is an obligate repressor of Hes1. We show that Ikaros-mediated repression is accomplished through direct binding within regulatory elements of Hes1 and provide evidence that Ikaros binds these sequences in a cooperative fashion with RBP-J. Therefore, we propose a novel mechanism of Notch target gene repression whereby is an repressor in the of In we show that the role of Ikaros in Hes1 repression contributes to the mechanism expression of CD4 in JE131 cells. Cell and Cell cells the of an Ikaros null mouse with T cell leukemia as described (6Kathrein K.L. Lorenz R. Minniti Innes A. Griffiths E. Winandy S. Mol. Cell. Biol. 2005; 25: 1645-1654Crossref PubMed Scopus (53) Google Scholar). in with and of inhibitor assays, of the inhibitor intracellular in or the to and by cell with with and for by of protein a and to a at for in in and with the at with for and with for at by with and to and described (6Kathrein K.L. Lorenz R. Minniti Innes A. Griffiths E. Winandy S. Mol. Cell. Biol. 2005; 25: 1645-1654Crossref PubMed Scopus (53) Google Scholar). Ikaros by 8: Google Scholar). and to for to and of sequences into at the of Cancer DNA Hes1 was a of Pear of and Cell into cells at and through a and at JE131 cells of cells with of in a at for at and cells with cells with the the expression as described (6Kathrein K.L. Lorenz R. Minniti Innes A. Griffiths E. Winandy S. Mol. Cell. Biol. 2005; 25: 1645-1654Crossref PubMed Scopus (53) Google Scholar). was the and was the and or cells in at to cells to cells and for cells by a was with JE131 cells or JE131 cells with for was a was a and of the and by DNA sequences are upon was JE131 cells with or at the cells to DNA by cells with for at and to with or the and and or a with or and the and by at DNA was by and by DNA and to the with and as to Hes1 Hes1 was with or was JE131 cells with or by in at for and to or of Ikaros in of Hes1 in an Ikaros T Cell with transcription Hes1, has been to expression of the T cell and the cell p27kip1 (22Kim H.K. Siu G. Mol. Cell. Biol. 1998; 18: 7166-7175Crossref PubMed Scopus (78) Google Scholar, 23Allen III, R.D. Kim H.K. Sarafova S.D. Siu G. Mol. Cell. Biol. 2001; 21: 3071-3082Crossref PubMed Scopus (51) Google Scholar, K. Hattori M. Hirai N. Shinozuka Y. Hirata H. Kageyama R. Sakai T. Minato N. Mol. Cell. Biol. 2005; 25: 4262-4271Crossref PubMed Scopus (177) Google Scholar). Interestingly, of Ikaros to the JE131 Ikaros null T leukemia cell line has been to both CD4 and p27kip1 (6Kathrein K.L. Lorenz R. Minniti Innes A. Griffiths E. Winandy S. Mol. Cell. Biol. 2005; 25: 1645-1654Crossref PubMed Scopus (53) Google Scholar). Therefore, we that of CD4 and p27kip1 in JE131 cells with Ikaros may be the of expression of Hes1. This repression of CD4 and to this Hes1 expression was in JE131 cells with the Ikaros or the of JE131 cells Ikaros of Hes1 expression. JE131 cells with a of Hes1 expression Notch signaling Hes1 suggesting that Hes1 expression in JE131 cells may Notch in these cells. In of it was that T leukemia cell mice with Ikaros expression (10Dumortier A. Jeannet R. Kirstetter P. Kleinmann E. Sellars M. dos Santos N.R. Thibault C. Barths J. Ghysdael J. Punt J.A. Kastner P. Chan S. Mol. Cell. Biol. 2006; 26: 209-220Crossref PubMed Scopus (134) Google constitutively express intracellular Notch the active of Therefore, JE131 cells for the of cell JE131 cells and by with an specific that was constitutively in JE131 cells is important to that the of in JE131 cells is likely to to deregulation of Hes1 expression in JE131 of Ikaros is sufficient to expression of Hes1. with of JE131 signaling is to and of many and T leukemia cell Lee C. Aster J.C. 2004; PubMed Scopus Google Scholar, W.S. Aster J.C. Curr. Opin. Hematol. 2004; 16: Scopus Google Scholar). The of and a of Hes1 expression in JE131 cells suggests that may function to promote the phenotype of these cells through the constitutive activation of Notch these we of was essential for of JE131 cells. these the inhibitor was cleavage of Notch, of and its to the nucleus. data have that of to mouse leukemia cell that express in and (10Dumortier A. Jeannet R. Kirstetter P. Kleinmann E. Sellars M. dos Santos N.R. Thibault C. Barths J. Ghysdael J. Punt J.A. Kastner P. Chan S. Mol. Cell. Biol. 2006; 26: 209-220Crossref PubMed Scopus (134) Google Scholar, J. J. K. Aster J.C. M. 2006; PubMed Scopus Google Scholar). In has been to be sufficient to induce cell and in leukemia cell with Notch1 J. J. K. Aster J.C. M. 2006; PubMed Scopus Google Scholar). However, of or to JE131 cells a their to the of by protein of In a in of was observed with Therefore, of are for and of JE131 cells. This is in to JE131 cells with which cell (6Kathrein K.L. Lorenz R. Minniti Innes A. Griffiths E. Winandy S. Mol. Cell. Biol. 2005; 25: 1645-1654Crossref PubMed Scopus (53) Google Scholar), suggesting that the of JE131 cells is upon of Ikaros of of to of Hes1 and of the T Cell that the observed in of was sufficient to Notch target gene Hes1 expression was was JE131 cells with or of JE131 cells with to a in Hes1 expression with that observed in cells with Therefore, the in that as a of was sufficient to Hes1 expression in JE131 was The phenotype of the JE131 at the of T cell development. of Ikaros in these cells a T of gene expression in which expression of T cell as CD4 and are up-regulated (6Kathrein K.L. Lorenz R. Minniti Innes A. Griffiths E. Winandy S. Mol. Cell. Biol. 2005; 25: 1645-1654Crossref PubMed Scopus (53) Google Scholar). Because Hes1 has been in repression of CD4 (22Kim H.K. Siu G. Mol. Cell. Biol. 1998; 18: 7166-7175Crossref PubMed Scopus (78) Google Scholar, 23Allen III, R.D. Kim H.K. Sarafova S.D. Siu G. Mol. Cell. Biol. 2001; 21: 3071-3082Crossref PubMed Scopus (51) Google and Hes1 expression we that JE131 cells in the of may CD4 as with JE131 cells with CD4 These data that of Notch signaling is sufficient to induce CD4 expression in JE131 in the of that this is the for of Hes1 in the of Ikaros with CD4 JE131 of Ikaros and with both in of CD4 and of Hes1, that in JE131 CD4 may repression of Hes1 by JE131 cells with Hes1 and Ikaros to expression of Hes1 in the of it be In JE131 expression of CD4 observed in JE131 cells with Ikaros with Hes1 Ikaros' to induce expression of CD4 These data provide evidence that of CD4 observed in JE131 cells is induced by repression of Hes1. Hes1 has been as a repressor of and p27kip1 upon expression of Ikaros in the Ikaros null JE131 cells (6Kathrein K.L. Lorenz R. Minniti Innes A. Griffiths E. Winandy S. Mol. Cell. Biol. 2005; 25: 1645-1654Crossref PubMed Scopus (53) Google Scholar). Therefore, of Hes1 may be the mechanism of p27kip1 in JE131 cells. this expression of p27kip1 in JE131 cells with Ikaros and Hes1 by p27kip1 expression in the of Ikaros and Hes1 with Ikaros Hes1 repression by Ikaros to the of p27kip1 in JE131 cells with role for Hes1 in regulating cell and has been (21Tomita K. Hattori M. Nakamura E. Nakanishi S. Minato N. Kageyama R. Genes Dev. 1999; 13: 1203-1210Crossref PubMed Scopus (182) Google Scholar, K. M. K. Nakanishi S. F. Kageyama R. 1996; 16: Full Text Full Text PDF PubMed Scopus Google Scholar, M. K. Y. K. Nakanishi S. Kageyama R. J. 13: PubMed Scopus Google Scholar). Therefore, we to of Hes1 by Ikaros the in observed in JE131 cells (6Kathrein K.L. Lorenz R. Minniti Innes A. Griffiths E. Winandy S. Mol. Cell. Biol. 2005; 25: 1645-1654Crossref PubMed Scopus (53) Google Scholar). However, this was the because JE131 cells similar to that observed in cells with Ikaros Interestingly, this with the of Hes1 expression to of p27kip1 expression of Hes1 Ikaros' DNA by which Ikaros Hes1 through direct binding to Hes1 regulatory or through with and of for Hes1 expression. to between these into two of Ikaros' DNA binding and that Ikaros' to bind at its DNA binding J. Georgopoulos K. J. Biol. 2002; Full Text Full Text PDF PubMed Scopus (67) Google Scholar). These Ikaros' be to its to with J. Georgopoulos K. J. Biol. 2002; Full Text Full Text PDF PubMed Scopus (67) Google of CD4 and in JE131 cells both Ikaros to Hes1 as by These data that of Hes1 expression in JE131 cells with Ikaros through DNA binding of Hes1 in the of in as a of both and These of DNA to transcription of these are with and which by or of Ikaros is to target these to specific gene of Hes1 expression in JE131 cells with Ikaros may Ikaros' to target to the Hes1 the of the Hes1 JE131 cells with the or Ikaros an was because Ikaros has been to a in in JE131 cells (6Kathrein K.L. Lorenz R. Minniti Innes A. Griffiths E. Winandy S. Mol. Cell. Biol. 2005; 25: 1645-1654Crossref PubMed Scopus (53) Google Scholar). of a in of at the Hes1 was observed in JE131 cells as with Ikaros These data that the of Ikaros in JE131 cells represses Hes1 expression by in at the Hes1 Ikaros to Hes1 in demonstrate direct Ikaros regulation of Hes1, Ikaros Because it has been that Ikaros and the Notch transcriptional can bind the same DNA sequences in electrophoretic mobility shift (10Dumortier A. Jeannet R. Kirstetter P. Kleinmann E. Sellars M. dos Santos N.R. Thibault C. Barths J. Ghysdael J. Punt J.A. Kastner P. Chan S. Mol. Cell. Biol. 2006; 26: 209-220Crossref PubMed Scopus (134) Google Scholar), to the Hes1 regulatory the identified binding Interestingly, this two binding in a was JE131 cells that been with Ikaros as as with the and was with In this it was that Ikaros binds directly within the Hes1 regulatory that has been to bind binding Although the binding for within Hes1 has been established by electrophoretic mobility shift (20Jarriault S. Brou C. Logeat F. Schroeter E.H. Kopan R. Israel A. Nature. 1995; 377: 355-358Crossref PubMed Scopus (1223) Google Scholar), Mol. Cell. 2004; 16: Full Text Full Text PDF PubMed Scopus Google Scholar), and R. T. Cell 1999; PubMed Scopus Google Scholar), this is the for Therefore, we two of the Ikaros binding within Hes1. of Ikaros binding was observed within the regulatory that also the binding Ikaros and to DNA in a Cell has been that because Ikaros and the same DNA binding they bind L.J. Capobianco A.J. Cancer Cell. 2003; 3: 551-564Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar). and Ikaros compete for binding within Hes1 regulatory binding within these sequences be in the of this was the binding was by with JE131 cells with Ikaros or the We the same in the regulatory of Hes1 as described to the of Ikaros of and Ikaros both to the Hes1 regulatory in JE131 cells with and binding in the of In binding was Ikaros was also a to Ikaros and bind DNA was by JE131 cells was with by of the protein of the and that both Ikaros and these data that Ikaros and can bind within of of and Ikaros' as a of Notch Genes to this of regulation to Notch target we Ikaros bind within potential regulatory sequences of the Notch target a whose expression is induced by Notch in thymocytes Immunity. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). of expression by in JE131 cells with Ikaros or expression upon of Ikaros to JE131 cells Although expression is as a for Notch its regulatory elements have been defined. Therefore, we sequences of the transcriptional for potential binding the within to to the of transcription was with and JE131 cells with Ikaros or the of Ikaros to was observed suggesting that Ikaros directly represses expression by binding to its regulatory was also with and JE131 cells with or with the Hes1 was within the regulatory only in the of Ikaros in and tumor suppressor genes in many forms of M. M. 2006; 8: PubMed Scopus Google Scholar, M. D. 2006; 8: PubMed Scopus Google Scholar, M. Curr. Opin. 1999; 15: PubMed Scopus Google Scholar, Curr. Opin. 1999; 15: PubMed Scopus Google Scholar). evidence that of a tumor suppressor and constitutive activation of Notch1, a this in the of leukemia (10Dumortier A. Jeannet R. Kirstetter P. Kleinmann E. Sellars M. dos Santos N.R. Thibault C. Barths J. Ghysdael J. Punt J.A. Kastner P. Chan S. Mol. Cell. Biol. 2006; 26: 209-220Crossref PubMed Scopus (134) Google Scholar, 11Beverly L.J. Capobianco A.J. Cancer Cell. 2003; 3: 551-564Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar, 12Beverly L.J. Capobianco A.J. Trends Mol. Med. 2004; 10: 591-598Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar, 13Lopez-Nieva P. Santos J. Fernandez-Piqueras J. Carcinogenesis. 2004; 25: 1299-1304Crossref PubMed Scopus (36) Google Scholar). is that Ikaros and Notch signaling also in regulation of normal T cell development. we provide evidence for a role for Ikaros in direct repression of Notch target by the role of Ikaros in repression of the Notch target Hes1. In this report, we have in the JE131 Ikaros null leukemia T cell Ikaros is for repression of Hes1. for these The first was that Ikaros with a for of Notch target gene expression it with this that Ikaros' DNA binding its These Ikaros' to Hes1, this Ikaros may compete for binding with and function as a repressor of Notch target However, evidence was that Ikaros and can both be with regulatory elements of Hes1 and these genes are suggesting that this mechanism is also The and we the mechanism is that Ikaros and bind to the regulatory of Hes1 and These data provide for the first that may the of DNA binding in this to gene expression. for of and in Notch gene in gene repression as we show has been suggested that the Notch Notch requires binding of a protein in with for Notch gene activation T. Kageyama R. Kopan R. J. Biol. 2006; Full Text Full Text PDF PubMed Scopus Google Scholar), it is unknown, to these two function We that the role of Ikaros in Notch target gene repression may be to of of the to regulatory elements by or to in DNA that DNA binding the Hes1 are two in Therefore, Ikaros and may bind to of these We that this is also the for the two binding in In the of the two are observed in Hes1. Interestingly, the with two of the DNA the which in in be the linear DNA be binding to Hes1 and regulatory was only observed Ikaros was One is that is in the of a in T the for the are it is the data that Ikaros and bind to repression of Hes1. This to Notch target suggesting it may be a mechanism for Notch target gene repression in developing T cells. are to this We that of Ikaros in as to of Notch target Therefore, constitutive of in Ikaros-deficient cells may expression of Notch target This is likely the mechanism cooperative Ikaros that identified in leukemia in which the L.J. Capobianco A.J. Cancer Cell. 2003; 3: 551-564Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar). Interestingly, both in Notch1 and Ikaros expression have been described in leukemia W.S. Aster J.C. Curr. Opin. Hematol. 2004; 16: Scopus Google Scholar, L. N. L. Wu C. A. M. U. S. A. 1999; PubMed Scopus Google Scholar, L. P.A. M. H. C. J. N. A. J. 1999; PubMed Scopus Google Scholar). The importance of expression to of leukemia cells has been through the of leukemia with Notch are to with Lee C. Aster J.C. 2004; PubMed Scopus Google Scholar). has that of a leukemia cell line in a mouse with a Ikaros (10Dumortier A. Jeannet R. Kirstetter P. Kleinmann E. Sellars M. dos Santos N.R. Thibault C. Barths J. Ghysdael J. Punt J.A. Kastner P. Chan S. Mol. Cell. Biol. 2006; 26: 209-220Crossref PubMed Scopus (134) Google Scholar). However, we demonstrate that the JE131 cell line is to with that it is for and be suggested that this is the of that have in these cells in However, it be that of JE131 cells can be and through of Ikaros by (6Kathrein K.L. Lorenz R. Minniti Innes A. Griffiths E. Winandy S. Mol. Cell. Biol. 2005; 25: 1645-1654Crossref PubMed Scopus (53) Google Scholar). These data that and of JE131 cells is by their of Ikaros constitutive of is likely that the of of Ikaros and constitutive to leukemia to These began with the that re-introduction of Ikaros into JE131 Ikaros null leukemia cells of the T cell and the cell We that of Hes1 expression may of CD4 and p27kip1 in JE131 because Hes1 is a to be in their regulation (22Kim H.K. Siu G. Mol. Cell. Biol. 1998; 18: 7166-7175Crossref PubMed Scopus (78) Google Scholar, 23Allen III, R.D. Kim H.K. Sarafova S.D. Siu G. Mol. Cell. Biol. 2001; 21: 3071-3082Crossref PubMed Scopus (51) Google Scholar, K. Hattori M. Hirai N. Shinozuka Y. Hirata H. Kageyama R. Sakai T. Minato N. Mol. Cell. Biol. 2005; 25: 4262-4271Crossref PubMed Scopus (177) Google Scholar). In this report, we demonstrate that expression of Hes1 in cells can with Ikaros' to induce expression of suggesting that Hes1 by Ikaros to Ikaros' to CD4 expression in these cells. These data also provide evidence for a role for Hes1 in of CD4 gene expression in developing The and transcriptional to be critically important for CD4 I. R. Mol. Cell. 2002; 10: Full Text Full Text PDF PubMed Scopus Google Scholar, I. M. T. T. Y. Cell. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar, I. 2004; PubMed Scopus Google Scholar), are also Notch target genes D. E. Genes Dev. 2005; PubMed Scopus Google Scholar). Because of Hes1 Ikaros' to induce of CD4 are to investigate of also to the mechanism Ikaros' role in regulation of CD4 expression. We Pear for the Hes1 and for with the for of the as as and Georgopoulos for
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