Oligomerization of RAR and AML1 transcription factors as a novel mechanism of oncogenic activation.
RAR and AML1 transcription factors are found in leukemias as fusion proteins with PML and ETO, respectively. Association of PML-RAR and AML1-ETO with the nuclear corepressor (N-CoR)/histone deacetylase (HDAC) complex is required to block hematopoietic differentiation. We show that PML-RAR and AML1-ETO exist in vivo within high molecular weight (HMW) nuclear complexes, reflecting their oligomeric state. Oligomerization requires PML or ETO coiled-coil regions and is responsible for abnormal recruitment of N-CoR, transcriptional repression, and impaired differentiation of primary hematopoietic precursors. Fusion of RAR to a heterologous oligomerization domain recapitulated the properties of PML-RAR, indicating that oligomerization per se is sufficient to achieve transforming potential. These results show that oligomerization of a transcription factor, imposing an altered interaction with transcriptional coregulators, represents a novel mechanism of oncogenic activation.
Pubmed ID: 10882117 RIS Download
Cell Transformation, Neoplastic | Core Binding Factor Alpha 2 Subunit | Histone Deacetylases | Humans | Leukemia | Leukemia, Myeloid | Leukemia, Promyelocytic, Acute | Neoplasm Proteins | Nuclear Proteins | Nuclear Receptor Co-Repressor 1 | Oncogene Proteins, Fusion | Peptide Fragments | Protein Binding | Protein Structure, Quaternary | Repressor Proteins | Response Elements | Transcription Factors | Transcription, Genetic | Tretinoin