Rbm15-Mkl1 Interacts with the Setd1b Histone H3-Lys4 Methyltransferase via a SPOC Domain That Is Required for Cytokine-Independent Proliferation 英文参考文献.docVIP

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Rbm15-Mkl1 Interacts with the Setd1b Histone H3-Lys4 Methyltransferase via a SPOC Domain That Is Required for Cytokine-Independent Proliferation 英文参考文献.doc

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Rbm15-Mkl1 Interacts with the Setd1b Histone H3-Lys4 Methyltransferase via a SPOC Domain That Is Required for Cytokine-Independent Proliferation 英文参考文献

Rbm15-Mkl1InteractswiththeSetd1bHistoneH3-Lys4 MethyltransferaseviaaSPOCDomainThatIsRequired forCytokine-IndependentProliferation Jeong-HeonLee1*,DavidG.Skalnik1,2* 1WellsCenterforPediatricResearch,DepartmentsofPediatricsandBiochemistryandMolecularBiology,IndianaUniversitySchoolofMedicine,Indianapolis,Indiana, UnitedStatesofAmerica,2DepartmentofBiology,IndianaUniversity-PurdueUniversityIndianapolisSchoolofScience,Indianapolis,Indiana,UnitedStatesofAmerica Abstract The Rbm15-Mkl1 fusion protein is associated with acute megakaryoblastic leukemia (AMKL), although little is known regardingthemolecularmechanism(s)wherebythisfusionproteincontributestoleukemogenesis.Here,weshowthatboth Rbm15andtheleukemogenicRbm15-Mkl1fusionproteininteractwiththeSetd1bhistoneH3-Lys4methyltransferase(also known as KMT2G). This interaction is direct and requires the Rbm15 SPOC domain and the Setd1b LSD motif. Over- expression of Rbm15-Mkl1 in the 6133 megakaryoblastic leukemia cell line, previously established by expression of the Rbm15-Mkl1 fusion protein in mice (Mercher et al., [2009] J. Clin. Invest. 119, 852–864), leads to decreased levels of endogenous Rbm15 and increased levels of endogenous Mkl1. These cells exhibit enhanced proliferation and cytokine- independentcellgrowth,whichrequiresanintactRbm15SPOCdomainthatmediatesinteractionbetweentheRbm15-Mkl1 fusion protein and the Setd1b methyltransferase. These results reveal altered Setd1b complex function and consequent alteredepigeneticregulationasapossiblemolecularmechanismthatmediatestheleukemogenicactivityoftheRbm15- Mkl1fusionproteininAMKL. Citation:LeeJ-H,SkalnikDG(2012)Rbm15-Mkl1InteractswiththeSetd1bHistoneH3-Lys4MethyltransferaseviaaSPOCDomainThatIsRequiredforCytokine- IndependentProliferation.PLoSONE7(8):e42965.doi:10.1371/journal.pone.0042965 Editor:Fre′de′riqueMagdinier,INSERMUMRS_910,France ReceivedMarch15,2012;AcceptedJuly16,2012;PublishedAugust21,2012 Copyright: ? 2012 Lee, Skalnik. This is an open-access article distribu