Forced homo-oligomerization of RARalpha leads to transformation of primary hematopoietic cells

Cancer Cell. 2006 Feb;9(2):95-108. doi: 10.1016/j.ccr.2006.01.005.

Abstract

Almost 100% of APL patients carry chimeric transcripts encoding truncated RARalpha fused to homo-oligomerization domains from partner proteins. To gain further insights into the cellular transformation mechanisms mediated by RARalpha fusion proteins, thorough structure/function analyses have been performed and identified the POZ homo-oligomerization domain as the minimal transformation domain that is necessary and sufficient for PLZF-RARalpha-mediated in vitro transformation of primary hematopoietic cells. A transformation-incompetent PLZF-RARalpha mutant defective in homo-oligomerization but not corepressor interaction could be rescued by synthetic FKBP-oligomerization domains. Furthermore, an artificial FKBP-RARalpha construct not only mimicked various biochemical properties of bona fide RARalpha fusion proteins but also mediated an ATRA-dependent transformation. Taken together, these findings endorse an oligomerization-dependent mechanism for RARalpha-mediated transformation and suggest a potential avenue for molecular therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biopolymers / chemistry
  • Biopolymers / metabolism
  • Cell Transformation, Neoplastic*
  • DNA-Binding Proteins / metabolism
  • Hematopoietic System / metabolism*
  • Hematopoietic System / pathology*
  • Mice
  • Mice, Inbred C57BL
  • Molecular Mimicry
  • Molecular Weight
  • Multiprotein Complexes / chemistry
  • Multiprotein Complexes / metabolism
  • Neoplasm Proteins / chemistry
  • Neoplasm Proteins / metabolism
  • Nuclear Receptor Co-Repressor 2
  • Oncogene Proteins, Fusion / chemistry
  • Oncogene Proteins, Fusion / metabolism
  • Phenotype
  • Point Mutation / genetics
  • Protein Binding
  • Protein Structure, Tertiary
  • Receptors, Retinoic Acid / chemistry*
  • Receptors, Retinoic Acid / genetics
  • Receptors, Retinoic Acid / metabolism*
  • Recombinant Fusion Proteins / chemistry
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism*
  • Repressor Proteins / metabolism
  • Retinoic Acid Receptor alpha

Substances

  • Biopolymers
  • DNA-Binding Proteins
  • Multiprotein Complexes
  • NCOR2 protein, human
  • Ncor2 protein, mouse
  • Neoplasm Proteins
  • Nuclear Receptor Co-Repressor 2
  • Oncogene Proteins, Fusion
  • PLZF-RARalpha fusion protein, human
  • RARA protein, human
  • Rara protein, mouse
  • Receptors, Retinoic Acid
  • Recombinant Fusion Proteins
  • Repressor Proteins
  • Retinoic Acid Receptor alpha