The inv(16) fusion protein associates with corepressors via a smooth muscle myosin heavy-chain domain

Kristie L. Durst, Bart Lutterbach, Tanawan Kummalue, Alan D. Friedman, Scott W. Hiebert

Research output: Contribution to journalArticlepeer-review

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 β to the coiled-coil region of a smooth muscle myosin heavy chain (CBFβ/SMMHC). CBFβ interacts with AML1 to form a heterodimer that binds DNA; this interaction increases the affinity of AML1 for DNA. The CBFβ/SMMHC fusion protein cooperates with AML1 to repress the transcription of AML1-regulated genes. We show that CBFβ/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 CBFβ/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.

Original languageEnglish (US)
Pages (from-to)607-619
Number of pages13
JournalMolecular and cellular biology
Volume23
Issue number2
DOIs
StatePublished - Jan 2003

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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