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The PML-retinoic acid receptor alpha translocation converts the receptor from an inhibitor to a retinoic acid-dependent activator of transcription factor AP-1

Abstract : We report here that the fusion of PML, a nuclear protein defined by the t(15;17) chromosomal translocation in acute promyelocytic leukemia, with retinoic acid receptor alpha (RAR alpha) changes the RAR alpha from a retinoic acid (RA)-dependent inhibitor to a RA-dependent activator of AP-1 transcriptional activity. The PML-RAR alpha chimera cooperates with c-Jun and, strikingly, with c-Fos to stimulate the transcription of both synthetic and natural reporter genes containing an AP-1 site. Stimulation is dependent on the concentration of RA and its dose-response curve is comparable to that for activation by RAR alpha of transcription on RA-responsive genes. Further, in the absence of RA, a circumstance in which RAR alpha has no effect on AP-1 activity, PML-RAR alpha is an inhibitor. Deletion of the dimerization, transactivation, or DNA-binding domains of c-Jun and removal of the PML dimerization domain in the PML-RAR alpha hybrid abrogates their transcriptional cooperatively. In view of the association between AP-1 activity and hemopoietic differentiation, we suggest that these properties of PML-RAR alpha could contribute to the leukemic phenotype and its response to RA.
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https://hal-pasteur.archives-ouvertes.fr/pasteur-03238309
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Submitted on : Thursday, May 27, 2021 - 9:04:17 AM
Last modification on : Friday, April 29, 2022 - 11:10:08 AM

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Vassilis Doucas, Jeremy Brockes, Moshe Yaniv, Hugues de Thé, Anne Dejean. The PML-retinoic acid receptor alpha translocation converts the receptor from an inhibitor to a retinoic acid-dependent activator of transcription factor AP-1. Proceedings of the National Academy of Sciences of the United States of America , National Academy of Sciences, 1993, 90 (20), pp.9345-9349. ⟨10.1073/pnas.90.20.9345⟩. ⟨pasteur-03238309⟩

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