The PML-retinoic acid receptor alpha translocation converts the receptor from an inhibitor to a retinoic acid-dependent activator of transcription factor AP-1.
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.
Doucas
V
V
Département des Biotechnologies, Institut Pasteur, Paris, France.
Brockes
J P
JP
Yaniv
M
M
de Thé
H
H
Dejean
A
A
D000818:Animals; D002460:Cell Line; D002522:Chlorocebus aethiops; D017364:Collagenases / Q000235:genetics; D005796:Genes; D006801:Humans; D066298:In Vitro Techniques; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011401:Promoter Regions, Genetic; D000071156:Promyelocytic Leukemia Protein; D016755:Proto-Oncogene Proteins c-jun / Q000502:physiology*; D018168:Receptors, Retinoic Acid / Q000737:chemistry* / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000502:physiology; D013329:Structure-Activity Relationship; D014157:Transcription Factors / Q000737:chemistry* / Q000235:genetics; D014178:Translocation, Genetic; D014212:Tretinoin / Q000378:metabolism; D025521:Tumor Suppressor Proteins
D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D000071156:Promyelocytic Leukemia Protein; D016755:Proto-Oncogene Proteins c-jun; D018168:Receptors, Retinoic Acid; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C070576:PML protein, human; D014212:Tretinoin; D017364:Collagenases