Oligomerization of RAR and AML1 transcription factors as a novel mechanism of oncogenic activation.

A Gobbi, P G Pelicci, C Nervi, N Landsberger, M A Lazar, X Hu, G Badaracco, I Schiavoni, E Colombo, A Bianchini, S Minucci, C Matteucci, S Giavara, L Di Croce, S Segalla, V Gelmetti, P De Luca, M Cioce, M Maccarana

Journal: Molecular cell 2000;5(5):811-20

PMID: 10882117

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Abstract

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.

Address: European Institute of Oncology, Department of Experimental Oncology, Milan, Italy. [email protected]

DOI: 10.1016/s1097-2765(00)80321-4