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, Nicoletta Landsberger, Clara Nervi, Pier Giuseppe Pelicci

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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.

Original languageEnglish
Pages (from-to)811-820
Number of pages10
JournalMolecular Cell
Volume5
Issue number5
DOIs
Publication statusPublished - 2000

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ASJC Scopus subject areas

  • Molecular Biology

Cite this

Minucci, S., Maccarana, M., Cioce, M., De Luca, P., Gelmetti, V., Segalla, S., Di Croce, L., Giavara, S., Matteucci, C., Gobbi, A., Bianchini, A., Colombo, E., Schiavoni, I., Badaracco, G., Hu, X., Lazar, M. A., Landsberger, N., Nervi, C., & Pelicci, P. G. (2000). Oligomerization of RAR and AML1 transcription factors as a novel mechanism of oncogenic activation. Molecular Cell, 5(5), 811-820. https://doi.org/10.1016/S1097-2765(00)80321-4