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.
Oligomerization of RAR and AML1 transcription factors as a novel mechanism of oncogenic activation / Saverio, Minucci; Marco, Maccarana; Mario, Cioce; Pasquale De, Luca; Vania, Gelmetti; Simona, Segalla; Luciano Di, Croce; Sabrina, Giavara; Cristian, Matteucci; Alberto, Gobbi; Andrea, Bianchini; Emanuela, Colombo; Ilaria, Schiavoni; Gianfranco, Badaracco; Xiao, Hu; Mitchell A., Lazar; N., Landesberger; Nervi, Clara; Pier Giuseppe, Pelicci. - In: MOLECULAR CELL. - ISSN 1097-2765. - STAMPA. - 5:5(2000), pp. 811-820. [10.1016/s1097-2765(00)80321-4]
Oligomerization of RAR and AML1 transcription factors as a novel mechanism of oncogenic activation
NERVI, Clara;
2000
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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
