RXR is an essential component of the oncogenic PML/RARA complex in vivo.
Although PML-enforced RARA homodimerization allows PML/RARA to bind DNA independently of its coreceptor RXR, the latter was identified within the PML/RARA complex. We demonstrate that a PML/RARA mutant defective for RXR binding fails to trigger APL development in transgenic mice, although it still transforms primary hematopoietic progenitors ex vivo. RXR enhances PML/RARA binding to DNA and is required for rexinoid-induced APL differentiation. In RA-treated PML/RARA-transformed cells, the absence of RXR binding results in monocytic, rather than granulocytic, differentiation. PML/RARA enhances posttranslational modifications of RXRA, including its sumoylation, suggesting that PML-bound sumoylation enzymes target RXRA and possibly other PML/RARA-bound chromatin proteins, further contributing to deregulated transcription. Thus, unexpectedly, RXR contributes to several critical aspects of in vivo transformation.
Zhu
Jun
J
CNRS/University Paris VII UMR 7151, laboratoire associé N11 de la Ligue contre le Cancer, Hôpital St. Louis, 1, avenue Claude Vellefaux, 75475 Paris Cedex 10, France.
Nasr
Rihab
R
Pérès
Laurent
L
Riaucoux-Lormière
Florence
F
Honoré
Nicole
N
Berthier
Caroline
C
Kamashev
Dmitrii
D
Zhou
Jun
J
Vitoux
Dominique
D
Lavau
Catherine
C
de Thé
Hugues
H
D000818:Animals; D051379:Mice; D008822:Mice, Transgenic; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology*; D009857:Oncogenes; D000071156:Promyelocytic Leukemia Protein; D011499:Protein Processing, Post-Translational; D018168:Receptors, Retinoic Acid / Q000502:physiology*; D000072482:Retinoic Acid Receptor alpha; D047488:Retinoid X Receptors / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000502:physiology*
D009687:Nuclear Proteins; C513293:Pml protein, mouse; D000071156:Promyelocytic Leukemia Protein; C000607072:Rara protein, mouse; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D047488:Retinoid X Receptors; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins