title: Oligomerization of RAR and AML1 transcription factors as a novel mechanism of oncogenic activation.
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.
authors.affiliation: European Institute of Oncology, Department of Experimental Oncology, Milan, Italy. sminucci@ieo.it
authors.forename: S
authors.initials: S
authors.lastname: Minucci
authors.forename: M
authors.initials: M
authors.lastname: Maccarana
authors.forename: M
authors.initials: M
authors.lastname: Cioce
authors.forename: P
authors.initials: P
authors.lastname: De Luca
authors.forename: V
authors.initials: V
authors.lastname: Gelmetti
authors.forename: S
authors.initials: S
authors.lastname: Segalla
authors.forename: L
authors.initials: L
authors.lastname: Di Croce
authors.forename: S
authors.initials: S
authors.lastname: Giavara
authors.forename: C
authors.initials: C
authors.lastname: Matteucci
authors.forename: A
authors.initials: A
authors.lastname: Gobbi
authors.forename: A
authors.initials: A
authors.lastname: Bianchini
authors.forename: E
authors.initials: E
authors.lastname: Colombo
authors.forename: I
authors.initials: I
authors.lastname: Schiavoni
authors.forename: G
authors.initials: G
authors.lastname: Badaracco
authors.forename: X
authors.initials: X
authors.lastname: Hu
authors.forename: M A
authors.initials: MA
authors.lastname: Lazar
authors.forename: N
authors.initials: N
authors.lastname: Landsberger
authors.forename: C
authors.initials: C
authors.lastname: Nervi
authors.forename: P G
authors.initials: PG
authors.lastname: Pelicci
mesh_terms: D002471:Cell Transformation, Neoplastic; D050676:Core Binding Factor Alpha 2 Subunit; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D007938:Leukemia / Q000209:etiology / Q000235:genetics*; D007951:Leukemia, Myeloid / Q000209:etiology / Q000235:genetics; D015473:Leukemia, Promyelocytic, Acute / Q000209:etiology / Q000235:genetics; D009363:Neoplasm Proteins / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism; D056971:Nuclear Receptor Co-Repressor 1; D015514:Oncogene Proteins, Fusion / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism; D011485:Protein Binding; D020836:Protein Structure, Quaternary; D000075142:RUNX1 Translocation Partner 1 Protein; D012097:Repressor Proteins / Q000378:metabolism; D020218:Response Elements; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D014212:Tretinoin
chemical_list: C107844:AML1-ETO fusion protein, human; D050676:Core Binding Factor Alpha 2 Subunit; C539127:NCOR1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D056971:Nuclear Receptor Co-Repressor 1; D015514:Oncogene Proteins, Fusion; D010446:Peptide Fragments; D000075142:RUNX1 Translocation Partner 1 Protein; D012097:Repressor Proteins; D014157:Transcription Factors; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; D014212:Tretinoin; D006655:Histone Deacetylases