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  • Title: The inv(16) fusion protein associates with corepressors via a smooth muscle myosin heavy-chain domain.
    Author: Durst KL, Lutterbach B, Kummalue T, Friedman AD, Hiebert SW.
    Journal: Mol Cell Biol; 2003 Jan; 23(2):607-19. PubMed ID: 12509458.
    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.
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