Recruitment of RXR by Homotetrameric RARα Fusion Proteins Is Essential for Transformation

Bernd B. Zeisig, Colin Kwok, Arthur Zelent, Pattabhiraman Shankaranarayanan, Hinrich Gronemeyer, Shuo Dong, Chi Wai Eric So

Research output: Contribution to journalArticlepeer-review

81 Scopus citations

Abstract

While formation of higher-order oncogenic transcriptional complexes is critical for RARα fusion proteins in acute promyelocytic leukemia, the essential components and their roles in mediating transformation are still largely unknown. To this end, the present study demonstrates that homodimerization is not sufficient for RARα fusion-mediated transformation, which requires higher-order homotetramerization. Surprisingly, intrinsic homo-oligomeric DNA binding by the fusion proteins is also dispensable. Importantly, higher-order RXR/RARα fusion hetero-oligomeric complexes that aberrantly recruit transcriptional corepressors to downstream targets are essential for transformation. Intervention of RXR-dependent pathways by panRXR-agonists or RXRα shRNAs suppresses RARα fusion-mediated transformation. Taken together, these results define the oncogenic threshold for self-association and reveal the pathological significance of higher-order RARα fusion/RXR hetero-oligomeric complexes and their potential value as a therapeutic target.

Original languageEnglish (US)
Pages (from-to)36-51
Number of pages16
JournalCancer Cell
Volume12
Issue number1
DOIs
StatePublished - Jul 10 2007

Keywords

  • CELLCYCLE
  • DNA

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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