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.
Mesh Terms:
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
Mol. Cell
Date: May. 01, 2000
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