title: MLL becomes functional through intra-molecular interaction not by proteolytic processing.
abstract: The mixed lineage leukemia (MLL) protein is an epigenetic transcriptional regulator that controls proliferative expansion of immature hematopoietic progenitors, whose aberrant activation triggers leukemogenesis. A mature MLL protein is produced by formation of an intra-molecular complex and proteolytic cleavage. However the biological significance of these two post-transcriptional events remains unclear. To address their in vivo roles, mouse mutant alleles were created that exclusively express either a variant protein incapable of intra-molecular interaction (designated de) or an uncleavable mutant protein (designated uc). The de homozygous mice died during midgestation and manifested devastating failure in embryonic development and reduced numbers of hematopoietic progenitors, whereas uc homozygous mice displayed no apparent defects. Expression of MLL target genes was severely impaired in de homozygous fibroblasts but unaffected in uc homozygous fibroblasts. These results unequivocally demonstrate that intra-molecular complex formation is a crucial maturation step whereas proteolytic cleavage is dispensable for MLL-dependent gene activation and proliferation in vivo.
authors.affiliation: Laboratory for Malignancy Control Research, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Yokoyama
authors.forename: Francesca
authors.initials: F
authors.lastname: Ficara
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Murphy
authors.forename: Christian
authors.initials: C
authors.lastname: Meisel
authors.forename: Chikako
authors.initials: C
authors.lastname: Hatanaka
authors.forename: Issay
authors.initials: I
authors.lastname: Kitabayashi
authors.forename: Michael L
authors.initials: ML
authors.lastname: Cleary
mesh_terms: D016475:3T3 Cells; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D049109:Cell Proliferation; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D057809:HEK293 Cells; D006410:Hematopoiesis / Q000235:genetics; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D017403:In Situ Hybridization; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009154:Mutation; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics* / Q000378:metabolism; D011485:Protein Binding; D059748:Proteolysis; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase; C497423:Kmt2a protein, mouse
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