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.
|Titolo:||Oligomerization of RAR and AML1 transcription factors as a novel mechanism of oncogenic activation|
|Parole Chiave:||Histone Deacetylases ; Humans ; Transcription, Genetic ; Leukemia, Myeloid ; Protein Binding ; Nuclear Receptor Co-Repressor 1 ; Protein Structure, Quaternary ; Leukemia ; Peptide Fragments ; Neoplasm Proteins ; Transcription Factors ; Nuclear Proteins ; Repressor Proteins ; Leukemia, Promyelocytic, Acute ; Tretinoin ; Core Binding Factor Alpha 2 Subunit ; Response Elements ; Cell Transformation, Neoplastic ; Oncogene Proteins, Fusion|
|Settore Scientifico Disciplinare:||Settore MED/04 - Patologia Generale|
|Data di pubblicazione:||mag-2000|
|Digital Object Identifier (DOI):||10.1016/S1097-2765(00)80321-4|
|Appare nelle tipologie:||01 - Articolo su periodico|