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

Mol Cell. 2000 May;5(5):811-20. doi: 10.1016/s1097-2765(00)80321-4.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Cell Transformation, Neoplastic*
  • Core Binding Factor Alpha 2 Subunit
  • Histone Deacetylases / metabolism
  • Humans
  • Leukemia / etiology
  • Leukemia / genetics*
  • Leukemia, Myeloid / etiology
  • Leukemia, Myeloid / genetics
  • Leukemia, Promyelocytic, Acute / etiology
  • Leukemia, Promyelocytic, Acute / genetics
  • Neoplasm Proteins / metabolism*
  • Nuclear Proteins / metabolism
  • Nuclear Receptor Co-Repressor 1
  • Oncogene Proteins, Fusion / metabolism*
  • Peptide Fragments / metabolism
  • Protein Binding
  • Protein Structure, Quaternary
  • RUNX1 Translocation Partner 1 Protein
  • Repressor Proteins / metabolism
  • Response Elements
  • Transcription Factors / metabolism*
  • Transcription, Genetic
  • Tretinoin

Substances

  • AML1-ETO fusion protein, human
  • Core Binding Factor Alpha 2 Subunit
  • NCOR1 protein, human
  • Neoplasm Proteins
  • Nuclear Proteins
  • Nuclear Receptor Co-Repressor 1
  • Oncogene Proteins, Fusion
  • Peptide Fragments
  • RUNX1 Translocation Partner 1 Protein
  • Repressor Proteins
  • Transcription Factors
  • promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein
  • Tretinoin
  • Histone Deacetylases