Dimerization-induced corepressor binding and relaxed DNA-binding specificity are critical for PML/RARA-induced immortalization

Jun Zhou; Laurent Pérès; Nicole Honoré; Rihab Nasr; Jun Zhu; Hugues de Thé

doi:10.1073/pnas.0603324103

Dimerization-induced corepressor binding and relaxed DNA-binding specificity are critical for PML/RARA-induced immortalization

Proc Natl Acad Sci U S A. 2006 Jun 13;103(24):9238-43. doi: 10.1073/pnas.0603324103. Epub 2006 Jun 6.

Authors

Jun Zhou¹, Laurent Pérès, Nicole Honoré, Rihab Nasr, Jun Zhu, Hugues de Thé

Affiliation

¹ Centre National de la Recherche Scientifique Unité Mixte de Recherche 7151, Université de Paris 7, Equipe labellisée par la Ligue Nationale contre le Cancer, Hôpital St. Louis, 1 Avenue C. Vellefaux, 75475 Paris Cedex 10, France.

Abstract

The pathogenesis of acute promyelocytic leukemia involves the transcriptional repression of master genes of myeloid differentiation by the promyelocytic leukemia-retinoic acid receptor alpha (PML/RARA) oncogene. PML-enforced RARA homodimerization allows the tighter binding of corepressors, silencing RARA target genes. In addition, homodimerization dramatically extends the spectrum of DNA-binding sites of the fusion protein compared with those of normal RARA. Yet, any contribution of these two properties of PML/RARA to differentiation arrest and immortalization of primary mouse hematopoietic progenitors was unknown. We demonstrate that dimerization-induced silencing mediator of retinoid and thyroid receptors (SMRT)-enhanced binding and relaxed DNA-binding site specificity are both required for efficient immortalization. Thus, enforced RARA dimerization is critical not only for triggering transcriptional repression but also for extending the repertoire of target genes. Our studies exemplify how dimerization-induced gain of functions converts an unessential transcription factor into a dominant oncogenic protein.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Binding Sites
Carrier Proteins / genetics
Carrier Proteins / metabolism
Cell Transformation, Neoplastic
Cells, Cultured
Co-Repressor Proteins
DNA / metabolism*
Dimerization
Fibroblasts / cytology
Fibroblasts / metabolism
Gene Expression Regulation
Genes, Neoplasm
Hematopoietic Stem Cells / cytology
Hematopoietic Stem Cells / physiology
Humans
Intracellular Signaling Peptides and Proteins / genetics
Intracellular Signaling Peptides and Proteins / metabolism
Leukemia, Promyelocytic, Acute
Mice
Mice, Inbred C57BL
Molecular Chaperones
Mutation
Neoplasm Proteins / chemistry*
Neoplasm Proteins / genetics
Neoplasm Proteins / metabolism*
Nuclear Proteins / genetics
Nuclear Proteins / metabolism
Oncogene Proteins, Fusion / chemistry*
Oncogene Proteins, Fusion / genetics
Oncogene Proteins, Fusion / metabolism*
Phenotype
Retinoid X Receptors / genetics
Retinoid X Receptors / metabolism

Substances

Carrier Proteins
Co-Repressor Proteins
Daxx protein, mouse
Intracellular Signaling Peptides and Proteins
Molecular Chaperones
Neoplasm Proteins
Nuclear Proteins
Oncogene Proteins, Fusion
Retinoid X Receptors
promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein
DNA