Leukemia proto-oncoprotein MLL forms a SET1-like histone methyltransferase complex with menin to regulate Hox gene expression.
MLL (for mixed-lineage leukemia) is a proto-oncogene that is mutated in a variety of human leukemias. Its product, a homolog of Drosophila melanogaster trithorax, displays intrinsic histone methyltransferase activity and functions genetically to maintain embryonic Hox gene expression. Here we report the biochemical purification of MLL and demonstrate that it associates with a cohort of proteins shared with the yeast and human SET1 histone methyltransferase complexes, including a homolog of Ash2, another Trx-G group protein. Two other members of the novel MLL complex identified here are host cell factor 1 (HCF-1), a transcriptional coregulator, and the related HCF-2, both of which specifically interact with a conserved binding motif in the MLL(N) (p300) subunit of MLL and provide a potential mechanism for regulating its antagonistic transcriptional properties. Menin, a product of the MEN1 tumor suppressor gene, is also a component of the 1-MDa MLL complex. Abrogation of menin expression phenocopies loss of MLL and reveals a critical role for menin in the maintenance of Hox gene expression. Oncogenic mutant forms of MLL retain an ability to interact with menin but not other identified complex components. These studies link the menin tumor suppressor protein with the MLL histone methyltransferase machinery, with implications for Hox gene expression in development and leukemia pathogenesis.
Yokoyama
Akihiko
A
Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Wang
Zhong
Z
Wysocka
Joanna
J
Sanyal
Mrinmoy
M
Aufiero
Deborah J
DJ
Kitabayashi
Issay
I
Herr
Winship
W
Cleary
Michael L
ML
D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000302:isolation & purification / Q000378:metabolism / Q000502:physiology*; D005786:Gene Expression Regulation; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000737:chemistry / Q000502:physiology*; D018398:Homeodomain Proteins / Q000096:biosynthesis / Q000235:genetics*; D051863:Host Cell Factor C1; D006801:Humans; D020014:K562 Cells; D007938:Leukemia / Q000209:etiology; D046911:Macromolecular Substances; D051788:Myeloid-Lymphoid Leukemia Protein; D011485:Protein Binding; D011496:Protein Methyltransferases; D011506:Proteins / Q000378:metabolism; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D011519:Proto-Oncogenes; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors / Q000378:metabolism
D004268:DNA-Binding Proteins; C497692:HCFC1 protein, human; C118856:HCFC2 protein, human; D018398:Homeodomain Proteins; D051863:Host Cell Factor C1; C497422:KMT2A protein, human; C000715470:MAS1 protein, human; C105373:MEN1 protein, human; D046911:Macromolecular Substances; D011506:Proteins; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors; C097899:homeobox protein HOXA9; D051788:Myeloid-Lymphoid Leukemia Protein; D000076983:Histone Methyltransferases; D011496:Protein Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; C411250:SET1 protein, S cerevisiae