Open AccessThe PML-retinoic acid receptor alpha translocation converts the receptor from an inhibitor to a retinoic acid-dependent activator of transcription factor AP-1.
Author(s) -
Vassilis Doucas,
Jeremy P. Brockes,
Moshe Yaniv,
Anne Dejean
Publication year - 1993
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.90.20.9345
Subject(s) - transactivation , retinoic acid receptor alpha , retinoic acid , retinoic acid receptor , acute promyelocytic leukemia , promyelocytic leukemia protein , transcription factor , microbiology and biotechnology , tretinoin , biology , activator (genetics) , transcription (linguistics) , cancer research , receptor , chemistry , biochemistry , gene , linguistics , philosophy
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.