title: The inv(16) fusion protein associates with corepressors via a smooth muscle myosin heavy-chain domain.
abstract: Inversion(16) is one of the most frequent chromosomal translocations found in acute myeloid leukemia (AML), occurring in over 8% of AML cases. This translocation results in a protein product that fuses the first 165 amino acids of core binding factor beta to the coiled-coil region of a smooth muscle myosin heavy chain (CBFbeta/SMMHC). CBFbeta interacts with AML1 to form a heterodimer that binds DNA; this interaction increases the affinity of AML1 for DNA. The CBFbeta/SMMHC fusion protein cooperates with AML1 to repress the transcription of AML1-regulated genes. We show that CBFbeta/SMMHC contains a repression domain in the C-terminal 163 amino acids of the SMMHC region that is required for inv(16)-mediated transcriptional repression. This minimal repression domain is sufficient for the association of CBFbeta/SMMHC with the mSin3A corepressor. In addition, the inv(16) fusion protein specifically associates with histone deacetylase 8 (HDAC8). inv(16)-mediated repression is sensitive to HDAC inhibitors. We propose a model whereby the inv(16) fusion protein associates with AML1 to convert AML1 into a constitutive transcriptional repressor.
authors.affiliation: Department of Biochemistry. Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
authors.forename: Kristie L
authors.initials: KL
authors.lastname: Durst
authors.forename: Bart
authors.initials: B
authors.lastname: Lutterbach
authors.forename: Tanawan
authors.initials: T
authors.lastname: Kummalue
authors.forename: Alan D
authors.initials: AD
authors.lastname: Friedman
authors.forename: Scott W
authors.initials: SW
authors.lastname: Hiebert
mesh_terms: D016475:3T3 Cells; D000818:Animals; D019556:COS Cells; D007446:Chromosome Inversion; D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins / Q000737:chemistry* / Q000378:metabolism; D019281:Dimerization; D017353:Gene Deletion; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009154:Mutation; D018995:Myosin Heavy Chains / Q000737:chemistry*; D015514:Oncogene Proteins, Fusion / Q000378:metabolism*; D010957:Plasmids / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins; D056264:Sin3 Histone Deacetylase and Corepressor Complex; D024745:Smooth Muscle Myosins / Q000737:chemistry*; D013347:Subcellular Fractions; D014157:Transcription Factors / Q000737:chemistry* / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection
chemical_list: D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins; D015514:Oncogene Proteins, Fusion; D011518:Proto-Oncogene Proteins; C493728:RUNX1 protein, human; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; C493726:Runx1 protein, mouse; C071731:SIN3 protein, S cerevisiae; C099683:SIN3A transcription factor; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors; C471254:inv(16) fusion protein, human; C409470:HDAC8 protein, human; D006655:Histone Deacetylases; D056264:Sin3 Histone Deacetylase and Corepressor Complex; D024745:Smooth Muscle Myosins; D018995:Myosin Heavy Chains