Role of RUNX Family Members in Transcriptional Repression and Gene Silencing

Role of RUNX family members in transcriptional repression and gene silencing

Kristie L Durst1 and Scott W Hiebert*,1,2

1Department of Biochemistry, Vanderbilt University School of Medicine, PRB 512, 23rd and Pierce, Nashville, TN 37232, USA; 2Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37232, USA

RUNX family members are DNA-binding transcription placed in the appropriate context, RUNX family factors that regulate the expression of genes involved in members act as organizing factors at the promoters cellular differentiation and cell cycle progression. The and enhancers of target genes where they associate with RUNX family includes three mammalian RUNX proteins cofactors and other DNA-binding transcription factors (RUNX1, -2, -3) and two homologues in Drosophila. that are required for gene regulation. These factors Experiments in Drosophila and mouse indicate that the include C/EBPa (Zhang et al., 1996; Westendorf et al., RUNX proteins are required for gene silencing of 1998), ETS family members (Giese et al., 1995; engrailed and CD4, respectively. RUNX-mediated repres- Petrovick et al., 1998; Kim et al., 1999; Mao et al., sion involves recruitment of corepressors such as mSin3A 1999), SMADs (Hanai et al., 1999; Gu et al., 2000; and Groucho as well as histone deacetylases. Further- Jakubowiak et al., 2000; Pardali et al., 2000; Zhang and more, RUNX1and RUNX3 associate with SUV39H1,a Derynck, 2000) and histone acetyltransferases including histone methyltransferase involved in gene silencing. p300/CBP (Kitabayashi et al., 1998; Pelletier et al., RUNX1is frequently targeted in human leukemia by 2002). chromosomal translocations that fuse the DNA-binding In contrast, the RUNX proteins are potent repressors domain of RUNX1to other transcription factors and of transcription even when expressed alone, suggesting corepressor molecules. The resulting leukemogenic fusion that their default function may be one of transcriptional proteins are transcriptional repressors that form stable repression. RUNX family members are required in vivo complexes with corepressors, histone deacetylases and for gene silencing of the CD4 promoter in mice and of histone methyltransferases. Thus, transcriptional repres- engrailed in Drosophila, which are among the best target sion and gene silencing through RUNX1contribute to the genes elucidated to date. This review focuses on the mechanisms of leukemogenesis of the fusion proteins. mechanisms of RUNX-dependent transcriptional Therapies directed at the associated cofactors may be repression. beneﬁcial for treatment of these leukemias. Oncogene (2004) 23, 4220–4224. doi:10.1038/sj.onc.1207122

Keywords: RUNX; AML; repression; transcription; Runt-mediated gene silencing silencing; histone deacetylases The founding member of this gene family is runt,a Drosophila pair-rule gene that controls segmentation in Introduction the Drosophila embryo and plays important roles in neurogenesis and sex determination (reviewed in Canon RUNX family members were initially implicated in and Banerjee, 2000). Thus, the effects of runt expression transcriptional activation, and indeed these factors bind and mutation can be studied by observing the resulting to core elements of enhancers and promoters that are segmentation patterns of the Drosophila embryo. required for the activation of a large number of genes. engrailed is a segment polarity gene that is potently RUNX proteins bind DNA as heterodimers with core repressed by Runt in the gastrula and germband binding factor b (CBFb), a non-DNA-binding subunit extension stages of embryogenesis. Using an inducible that increases the afﬁnity of RUNX factors for DNA runt, even moderate levels of Runt led to constitutive (Ogawa et al., 1993; Wang et al., 1993). The RUNX repression of engrailed and embryonic lethality (Wheeler proteins are poor activators on their own, even though et al., 2002). Taking advantage of these phenotypes, a they are able to interact with transcriptional coactiva- genetic screen was performed for factors that are tors such as histone acetyltransferases. However, when required for repression by Runt. Four proteins had dose-dependent effects on Runt- mediated repression in this assay. These included *Correspondence: SW Hiebert, Department of Biochemistry, Vander- bilt University School of Medicine, PRB 512, 23rd and Pierce, Tramtrack (Ttk), a DNA-binding transcriptional re- Nashville, TN 37232, USA; pressor, the transcriptional corepressors dCtBP and E-mail: [email protected] Groucho, and the histone deacetylase Rpd3 (Wheeler RUNX factors are transcriptional repressors KL Durst and SW Hiebert 4221 et al., 2002). Embryos that were derived from females Runx binding site in the silencer core sequence was heterozygous for tramtrack restored engrailed expres- replaced by the GAL4 DNA-binding site (Taniuchi sion in the gastrula stage in the presence of ectopic et al., 2002). Runt. In contrast, those that were derived from females The essential role of RUNX family proteins in CD4 expressing mutant Groucho and Rpd3 showed repres- silencing was demonstrated genetically. As deletion of sion of engrailed mRNA in the gastrula stage but did not the Runx genes can cause embryonic or neonatal maintain this repression during germband extension. lethality (Okuda et al., 1996; Wang et al., 1996; Komori Rpd3 was not required for establishment of engrailed et al., 1997; Li et al., 2002), T cells were analysed in mice repression by Runt; however, maintenance of repression reconstituted with hematopoietic stem cells from the in the germband extension stage was sensitive to fetal livers of embryos lacking the Runx genes (2 and 3) decreased Rpd3 activity. Recruitment of Groucho was or by using conditional recombination to remove not necessary for Runt-mediated repression at the Runx1. When immunodeﬁcient mice lacking the recom- blastoderm stage but was required for maintenance of binase Rag2 were reconstituted with fetal liver cells from this repression during germband extension (Wheeler Runx3À/À mice, CD4 was derepressed in the peripheral et al., 2002). Thus, there is a distinction between cytotoxic T cells (Taniuchi et al., 2002). Similar results establishment and maintenance of Runt-dependent were obtained using a strain of Runx3 knockout mice repression. that are viable for several months (Levanon et al., 2002). Unexpectedly, DNA binding was not required for These mice displayed reduced numbers of CD8 þ T cells Runt to cooperate with Ttk (Wheeler et al., 2002). Thus, in the thymus and in the circulating T-cell population Runt may also be capable of functioning as a along with increased expression of CD4 in the peripheral corepressor for Ttk and may be recruited by Ttk to CD8 þ cells (Woolf et al., 2003). In contrast, mice that the promoters of Ttk-regulated genes to repress were reconstituted with fetal liver cells from Runx2À/À transcription in the gastrula stage. However, mainte- mice displayed normal CD4 and CD8 expression on nance of repression requires DNA binding of Runt at peripheral T cells (Taniuchi et al., 2002). Thus, Runx3, the promoter and further recruitment of the Groucho/ but not Runx2, is required for the establishment of CD4 Rpd3 complex (Wheeler et al., 2002). Rpd3 likely silencing in the progression from double-positive to prevents activation through its histone deacetylase single-positive T cells (Figure 1). activity, which alters the local chromatin structure and Normal CD4 silencing was observed in peripheral thwarts access to activating factors and transcriptional CD8 þ T cells when Runx1 was removed from the T initiation machinery. cells of mice using Cre recombinase expressed from the Lck promoter (Taniuchi et al., 2002). However, more studies are needed to examine the function of Runx1 in peripheral T cells given that a large percentage of Runx-mediated gene silencing in mice

RUNX factors are also required for gene silencing in mice. CD4 is a T-cell surface antigen that is a marker of thymocyte differentiation. Thymocyte differentiation involves several distinct steps that are marked by expression of the cell surface markers CD4 and CD8. Hematopoietic precursors differentiate into double- negative thymocytes (CD4ÀCD8À), progress through a double-positive stage (CD4 þ CD8 þ ), and are selected for either CD4 or CD8 expression by silencing of one of these genes (Figure 1). These single-positive thymocytes exit the thymus and have distinct actions in the periphery as CD4 þ helper cells or CD8 þ cytotoxic T cells. Mutagenesis of the regulatory element required for CD4 silencing during T-cell development identiﬁed two Runx consensus DNA-binding sites as required sequences, and Runx1 bound to both motifs (Taniuchi et al., 2002). Chimeric mice containing mutations in the primary Runx binding site within the core sequence had variegated derepression of CD4 in 18–30% of mature CD8 þ T cells. Furthermore, mutation of the second Figure 1 Runx1 and Runx3 are required for CD4 silencing in vivo. Runx binding site resulted in full derepression of CD4 in Runx1 binds the CD4 silencer and is required to repress these cells. Mutation of the two binding sites also transcription in immature double-negative (DN) thymocytes. resulted in partial derepression of CD4 in double- Runx1 is also required for activation of CD8 as the DN population progresses into double-positive (DP) thymocytes. Runx3 estab- negative thymocytes. Runx1 and Runx3, when fused to lishes epigenetic silencing in CD4ÀCD8 þ cytotoxic T cells by the GAL4 DNA-binding domain, were also able to binding the CD4 silencer core sequence. Runx1 may also be actively repress transcription of a reporter in which the involved in CD4 silencing in CD8 þ T cells

Oncogene RUNX factors are transcriptional repressors KL Durst and SW Hiebert 4222 splenocytes retained Runx1 expression. In contrast, a of the Groucho binding domain in RUNX1 did not role for Runx1 in double-negative thymocyte matura- impair repression in this assay. In contrast, a deletion tion was elucidated. The lack of Runx1 resulted in that impaired the recruitment of mSin3A ablated upregulation of CD4 expression in a TCRblo immature repression of the p21 promoter by RUNX1 (Lutterbach thymocyte population (Taniuchi et al., 2002). These et al., 2000). mSin3A recruits histone deacetylases results were similar to that of mice with deletions of the (Laherty et al., 1997), and treatment of RUNX1- Runx binding sites in the CD4 silencer sequence. The expressing NIH3T3 cells with a broad-spectrum histone mice displayed low numbers of total thymocytes and a deacetylase inhibitor, Trichostatin A, impaired repres- higher percentage of thymocytes with low or absent sion by RUNX1 implying that histone deacetylases expression of CD8 (Taniuchi et al., 2002). In addition, contributed to RUNX1-mediated repression. haploinsufficiency of Runx1 in Runx3 null mice resulted Maintenance of repression was sensitive to decreased in complete loss of CD8 þ T cells due to CD4 Rpd3 histone deacetylase activity in Drosophila (Wheel- derepression in these cells (Woolf et al., 2003). Thus, er et al., 2002), but the mechanism was unknown. Runx1 cooperates with Runx3 to regulate T-cell RUNX2 copurified with HDAC6, but not with HDACs development through CD4 silencing, and Runx1 is 2, 4 and 5, suggesting direct recruitment of this HDAC required for CD4 silencing in double-negative thymo- (Westendorf et al., 2002). The C-terminal domain of cytes (Figure 1). RUNX2 contains a potent repression domain that is also required for association with HDAC6. However, there are HDAC-dependent as well as -independent mechanisms of transcriptional repression, as TSA Mechanisms of repression completely inhibited repression by aa 383–498 of RUNX2 but only partially inhibited repression by aa Insights into the mechanisms of repression by RUNX 383–513 (Westendorf et al., 2002). This domain was also family members have been derived from analogies to required for localization of HDAC6 to the chromatin, Drosophila corepressors and from studies of chromoso- and HDAC6 coimmunoprecipitated with RUNX2 in mal translocation fusion proteins that affect RUNX1. osteoblasts where RUNX2 is required for development Repression and activation by RUNX family members is and differentiation. These data imply that HDAC6 is cell-type specific and depends on associated cofactors. required for RUNX2-mediated repression and demon- One of the first corepressors that was found to bind to strate a physical interaction between HDAC6 and RUNX factors is the human Groucho homologue TLE RUNX2 (Figure 2). (Aronson et al., 1997; Imai et al., 1998; Javed et al., In order to determine whether RUNX1 could directly 2000). The associations between RUNX factors and associate with histone deacetylases, Cos7 cells were Groucho/TLE are relatively weak in that they were cotransfected with cDNAs encoding RUNX1 and observed only in yeast two-hybrid and in vitro assays. In epitope-tagged HDACs1-9 and were immunoprecipi- addition, Groucho-independent mechanisms of repres- tated with antibodies to the tags. RUNX1 associated sion were identified (Aronson et al., 1997). Therefore, strongly with HDACs 1, 3 and 9 and weakly with Groucho/TLE family members may be promoter- specific corepressors for the RUNX factors. The identification of other corepressors and histone deacetylases (HDACs) that are recruited by RUNX family members was based on studies of the chromosomal translocation fusion proteins that retain a portion of RUNX1. The t(8;21) fusion protein recruits mSin3A and mSin3B through at least two domains encoded by the gene from chromosome 8 known as ETO or MTG8 (Lutterbach et al., 1998; Amann et al., 2001). Mutagen- esis studies indicated that RUNX1 could also associate with mSin3A. Indeed, endogenous RUNX1 copurified with mSin3A in cells that were metabolically labeled and immunoprecipitated with an antibody directed to endogenous mSin3A (Lutterbach et al., 2000). RUNX2 and RUNX3 also coimmunoprecipitated with mSin3 (Figure 2). The mSin3 interaction domain of RUNX1 was mapped to the region just C-terminal to the Runt Figure 2 RUNX family members recruit corepressors, HDACs and SUV39H1 to repress transcription. RUNX family members homology domain as deletion of amino acids (aa) 208– recruit the Groucho homologue TLE to their C-terminal domains 237 impaired the association. Studies on the transcrip- that contain the Groucho-binding motif VWRPY. They also tional activity of RUNX proteins in NIH3T3 cells associate with the mSin3 corepressors that recruit HDACs 1 and 2. Binding of mSin3 is required for RUNX1-mediated repression of indicated that RUNX1 repressed transcription in these Waf1/Cip1 waf1/cip1 the p21 promoter in NIH3T3 cells. RUNX1 associates cells. For example, the p21 promoter contains four strongly with HDACs 1, 3 and 9 and weakly with HDACs 2, 5 and perfect RUNX1 DNA-binding sites and was potently 6. RUNX2 binds HDAC6. RUNX1 and RUNX3 recruit repressed by Runx1 (Lutterbach et al., 2000). Removal SUV39H1 to repress transcription. RHD, runt homology domain

Oncogene RUNX factors are transcriptional repressors KL Durst and SW Hiebert 4223 HDACs 2, 5, and 6 (Durst et al., 2003) (Figure 2). These include the t(8:21) that fuses the DNA-binding domain data suggest that HDACs are directly involved in the of RUNX1 to the corepressor ETO and the t(12;21) that mechanism of repression by RUNX1 and that RUNX fuses the N-terminus of TEL to most of RUNX1 family members recruit distinct HDACs for repression. (Miyoshi et al., 1991; Erickson et al., 1992; Golub et al., RUNX family members are required not only for 1995). In addition, the inv(16) targets the RUNX1 transcriptional repression, but for gene silencing in binding partner CBFb and fuses it to the coiled-coil Drosophila and mice (Wheeler et al., 2000; Taniuchi domain of a smooth muscle myosin heavy chain (Liu et al., 2002), which has stimulated a search for RUNX- et al., 1993). In each of these cases, the fusion protein recruited factors that function in long-term gene recruits corepressors and HDACs to create stable, silencing. SUV39H1 is a histone H3 lysine 9 speciﬁc constitutive repression complexes at the promoters of methyltransferase (Rea et al., 2000). Methylation of RUNX1 target genes (Gelmetti et al., 1998; Lutterbach lysine 9 of histone H3 is a post-translational modiﬁca- et al., 1998; Wang et al., 1998; Fenrick et al., 1999; tion that allows the binding of heterochromatin protein- Guidez et al., 2000; Amann et al., 2001; Wang and 1 (HP1) to silence gene expression (Bannister et al., Hiebert, 2001; Durst et al., 2003). The stable association 2001; Lachner et al., 2001; Nakayama et al., 2001). of the fusion proteins with corepressors requires the Coimmunoprecipitation experiments were performed in RUNX1 domains that also contact corepressors. This is Cos7 cells cotransfected with cDNAs encoding especially the case for the t(12;21) fusion protein TEL/ RUNX1, -2 or -3 and SUV39H1. RUNX1 and RUNX3 AML1 in which both fusion partners bind to mSin3A, associated with SUV39H1 (Reed-Inderbitzen et al., and the resulting fusion protein binds to mSin3A with unpublished data). Interestingly, both Runx1 and very high stoichiometry (Fenrick et al., 1999). Therefore, Runx3 were required for silencing of CD4 during T- constitutive repression of RUNX1 target genes, as cell development (Taniuchi et al., 2002). However, opposed to the conditional activation or repression by Runx2 was not required for silencing at the CD4 locus the wild-type RUNX1 protein, appears to contribute to (Taniuchi et al., 2002) and did not associate with leukemogenesis by the fusion proteins. SUV39H1 in these assays. In addition, at least one of the Given that DNA-binding transcription factors do not SUV39H1 binding domains in RUNX1 is also required appear to be useful targets for the development of small for RUNX1-mediated repression of p21Waf1/Cip1. Thus, molecule inhibitors for therapeutic intervention in the mechanism of repression by RUNX proteins cancer, RUNX1-associated factors may prove to be involves transcriptional corepressors, such as mSin3A, useful secondary targets for the development of HDACs, and gene silencing factors including SUV39H1 therapies. The enzymatic activities of HDACs and (Figure 2). histone methyltransferases are attractive targets, and HDAC inhibitors such as phenyl butyrate and depsi- Contribution of repression domains to translocation fusion peptide are already being tested in the clinic. It is proteins in acute leukemia possible that these agents will re-activate target genes, including the p14ARF tumor suppressor (Linggi et al., The chromosomal translocations involving RUNX1 are 2002), that may cause growth arrest and apoptosis in among the most frequent in human leukemia. These leukemic cells.

References

Amann JM, Nip J, Strom DK, Lutterbach B, Harada H, Golub TR, Barker GF, Bohlander SK, Hiebert SW, Ward DC, Lenny N, Downing JR, Meyers S and Hiebert SW. (2001). Bray-Ward P, Morgan E, Raimondi SC, Rowley JD and Mol. Cell. Biol., 21, 6470–6483. Gilliland DG. (1995). Proc. Natl. Acad. Sci. USA, 92, Aronson BD, Fisher AL, Blechman K, Caudy M and Gergen 4917–4921. JP. (1997). Mol. Cell. Biol., 17, 5581–5587. Gu TL, Goetz TL, Graves BJ and Speck NA. (2000). Mol. Bannister AJ, Zegerman P, Partridge JF, Miska EA, Thomas Cell. Biol., 20, 91–103. JO, Allshire RC and Kouzarides T. (2001). Nature, 410, Guidez F, Petrie K, Ford AM, Lu H, Bennett CA, 120–124. MacGregor A, Hannemann J, Ito Y, Ghysdael J, Greaves Canon J and Banerjee U. (2000). Semin. Cell Dev. Biol., 11, M, Wiedemann LM and Zelent A. (2000). Blood, 96, 327–336. 2557–2561. Durst KL, Lutterbach B, Kummalue T, Friedman AD and Hanai J, Chen LF, Kanno T, Ohtani-Fujita N, Kim WY, Hiebert SW. (2003). Mol. Cell. Biol., 23, 607–619. Guo WH, Imamura T, Ishidou Y, Fukuchi M, Shi MJ, Erickson P, Gao J, Chang KS, Look T, Whisenant E, Stavnezer J, Kawabata M, Miyazono K and Ito Y. (1999). Raimondi S, Lasher R, Trujillo J, Rowley J and Drabkin J. Biol. Chem., 274, 31577–31582. H. (1992). Blood, 80, 1825–1831. Imai Y, Kurokawa M, Tanaka K, Friedman AD, Ogawa S, Fenrick R, Amann JM, Lutterbach B, Wang L, Westendorf JJ, Mitani K, Yazaki Y and Hirai H. (1998). Biochem. Biophys. Downing JR and Hiebert SW. (1999). Mol. Cell. Biol., 19, Res. Commun., 252, 582–589. 6566–6574. Jakubowiak A, Pouponnot C, Berguido F, Frank R, Mao S, Gelmetti V, Zhang J, Fanelli M, Minucci S, Pelicci PG and Massague J and Nimer SD. (2000). J. Biol. Chem., 275, Lazar MA. (1998). Mol. Cell. Biol., 18, 7185–7191. 40282–40287. Giese K, Kingsley C, Kirshner JR and Grosschedl R. (1995). Javed A, Guo B, Hiebert S, Choi JY, Green J, Zhao SC, Genes Dev., 9, 995–1008. Osborne MA, Stifani S, Stein JL, Lian JB, van Wijnen AJ

Oncogene RUNX factors are transcriptional repressors KL Durst and SW Hiebert 4224 and Stein GS. (2000). J. Cell Sci., 113 (Part 12), Ogawa E, Inuzuka M, Maruyama M, Satake M, Naito-Fujimoto 2221–2231. M, Ito Y and Shigesada K. (1993). Virology, 194, 314–331. Kim WY, Sieweke M, Ogawa E, Wee HJ, Englmeier U, Graf T Okuda T, van Deursen J, Hiebert SW, Grosveld G and and Ito Y. (1999). EMBO J., 18, 1609–1620. Downing JR. (1996). Cell, 84, 321–330. Kitabayashi I, Yokoyama A, Shimizu K and Ohki M. (1998). Pardali E, Xie XQ, Tsapogas P, Itoh S, Arvanitidis K, Heldin EMBO J., 17, 2994–3004. CH, ten Dijke P, Grundstrom T and Sideras P. (2000). Komori T, Yagi H, Nomura S, Yamaguchi A, Sasaki K, J. Biol. Chem., 275, 3552–3560. Deguchi K, Shimizu Y, Bronson RT, Gao YH, Inada M, Pelletier N, Champagne N, Stifani S and Yang XJ. (2002). Sato M, Okamoto R, Kitamura Y, Yoshiki S and Kishimoto Oncogene, 21, 2729–2740. T. (1997). Cell, 89, 755–764. Petrovick MS, Hiebert SW, Friedman AD, Hetherington CJ, Lachner M, O’Carroll D, Rea S, Mechtler K and Jenuwein T. Tenen DG and Zhang DE. (1998). Mol. Cell. Biol., 18, (2001). Nature, 410, 116–120. 3915–3925. Laherty CD, Yang WM, Sun JM, Davie JR, Seto E and Rea S, Eisenhaber F, O’Carroll D, Strahl BD, Sun ZW, Eisenman RN. (1997). Cell, 89, 349–356. Schmid M, Opravil S, Mechtler K, Ponting CP, Allis CD Levanon D, Bettoun D, Harris-Cerruti C, Woolf E, Negreanu and Jenuwein T. (2000). Nature, 406, 593–599. V, Eilam R, Bernstein Y, Goldenberg D, Xiao C, Fliegauf Taniuchi I, Osato M, Egawa T, Sunshine MJ, Bae SC, Komori M, Kremer E, Otto F, Brenner O, Lev-Tov A and Groner Y. T, Ito Y and Littman DR. (2002). Cell, 111, 621–633. (2002). EMBO J., 21, 3454–3463. Wang J, Hoshino T, Redner RL, Kajigaya S and Liu JM. Li QL, Ito K, Sakakura C, Fukamachi H, Inoue K, Chi XZ, (1998). Proc. Natl. Acad. Sci. USA, 95, 10860–10865. Lee KY, Nomura S, Lee CW, Han SB, Kim HM, Kim WJ, Wang L and Hiebert SW. (2001). Oncogene, 20, 3716–3725. Yamamoto H, Yamashita N, Yano T, Ikeda T, Itohara S, Wang Q, Stacy T, Binder M, Marin-Padilla M, Sharpe AH Inazawa J, Abe T, Hagiwara A, Yamagishi H, Ooe A, and Speck NA. (1996). Proc. Natl. Acad. Sci. USA, 93, Kaneda A, Sugimura T, Ushijima T, Bae SC and Ito Y. 3444–3449. (2002). Cell, 109, 113–124. Wang S, Wang Q, Crute BE, Melnikova IN, Keller SR and Linggi B, Muller-Tidow C, Van De Locht L, Hu M, Nip J, Speck NA. (1993). Mol. Cell. Biol., 13, 3324–3339. Serve H, Berdel WE, Van Der Reijden B, Quelle DE, Westendorf JJ, Yamamoto CM, Lenny N, Downing JR, Rowley JD, Cleveland J, Jansen JH, Pandolﬁ PP and Selsted ME and Hiebert SW. (1998). Mol. Cell. Biol., 18, Hiebert SW. (2002). Nat. Med., 8, 743–750. 322–333. Liu P, Tarle SA, Hajra A, Claxton DF, Marlton P, Freedman Westendorf JJ, Zaidi SK, Cascino JE, Kahler R, van Wijnen M, Siciliano MJ and Collins FS. (1993). Science, 261, AJ, Lian JB, Yoshida M, Stein GS and Li X. (2002). 1041–1044. Mol. Cell. Biol., 22, 7982–7992. Lutterbach B, Westendorf JJ, Linggi B, Isaac S, Seto E and Wheeler JC, Shigesada K, Gergen JP and Ito Y. (2000). Semin. Hiebert SW. (2000). J. Biol. Chem., 275, 651–656. Cell Dev. Biol., 11, 369–375. Lutterbach B, Westendorf JJ, Linggi B, Patten A, Moniwa M, Wheeler JC, VanderZwan C, Xu X, Swantek D, Tracey WD Davie JR, Huynh KD, Bardwell VJ, Lavinsky RM, and Gergen JP. (2002). Nat. Genet., 32, 206–210. Rosenfeld MG, Glass C, Seto E and Hiebert SW. (1998). Woolf E, Xiao C, Fainaru O, Lotem J, Rosen D, Negreanu V, Mol. Cell. Biol., 18, 7176–7184. Bernstein Y, Goldenberg D, Brenner O, Berke G, Levanon Mao S, Frank RC, Zhang J, Miyazaki Y and Nimer SD. D and Groner Y. (2003). Proc. Natl. Acad. Sci. USA, 100, (1999). Mol. Cell. Biol., 19, 3635–3644. 7731–7736. Miyoshi H, Shimizu K, Kozu T, Maseki N, Kaneko Y and Zhang DE, Hetherington CJ, Meyers S, Rhoades KL, Larson Ohki M. (1991). Proc. Natl. Acad. Sci. USA, 88, 10431– CJ, Chen HM, Hiebert SW and Tenen DG. (1996). Mol. 10434. Cell. Biol., 16, 1231–1240. Nakayama J, Rice JC, Strahl BD, Allis CD and Grewal SI. Zhang Y and Derynck R. (2000). J. Biol. Chem., 275, 16979– (2001). Science, 292, 110–113. 16985.

Oncogene