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

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.

Pubmed ID: 10882117

Authors

  • 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 MA
  • Landsberger N
  • Nervi C
  • Pelicci PG

Journal

Molecular cell

Publication Data

May 13, 2000

Associated Grants

  • Agency: NIDDK NIH HHS, Id: DK45586

Mesh Terms

  • Cell Transformation, Neoplastic
  • Core Binding Factor Alpha 2 Subunit
  • Histone Deacetylases
  • Humans
  • Leukemia
  • Leukemia, Myeloid
  • Leukemia, Promyelocytic, Acute
  • Neoplasm Proteins
  • Nuclear Proteins
  • Nuclear Receptor Co-Repressor 1
  • Oncogene Proteins, Fusion
  • Peptide Fragments
  • Protein Binding
  • Protein Structure, Quaternary
  • Repressor Proteins
  • Response Elements
  • Transcription Factors
  • Transcription, Genetic
  • Tretinoin