期刊
MOLECULAR AND CELLULAR BIOLOGY
卷 23, 期 2, 页码 607-619出版社
AMER SOC MICROBIOLOGY
DOI: 10.1128/MCB.23.2.607-619.2003
关键词
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资金
- NCI NIH HHS [R01 CA077274, R01-CA77274, R01-CA87549, P30 CA068485, CA68485, R01 CA087549, R01-CA64140, R01 CA064140] Funding Source: Medline
- NATIONAL CANCER INSTITUTE [R01CA087549, R01CA064140, R01CA077274, P30CA068485] Funding Source: NIH RePORTER
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 0 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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