THE PML RETINOIC ACID RECEPTOR-ALPHA TRANSLOCATION CONVERTS THE RECEPTOR FROM AN INHIBITOR TO A RETINOIC ACID-DEPENDENT ACTIVATOR OF TRANSCRIPTION FACTOR-AP-1
V. Doucas et al., 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 Statesof America, 90(20), 1993, pp. 9345-9349
We report here that the fusion of PML, a nuclear protein defined by th
e t(15;17) chromosomal translocation in acute promyelocytic leukemia,
with retinoic acid receptor alpha (RARalpha) changes the RARalpha from
a retinoic acid (RA)-dependent inhibitor to a RA-dependent activator
of AP-1 transcriptional activity. The PML-RARalpha 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-respo
nse curve is comparable to that for activation by RARalpha of transcri
ption on RA-responsive genes. Further, in the absence of RA, a circums
tance in which RARalpha has no effect on AP-1 activity, PML-RARalpha i
s an inhibitor. Deletion of the dimerization, transactivation, or DNA-
binding domains of c-Jun and removal of the PML dimerization domain in
the PML-RARalpha hybrid abrogates their transcriptional cooperativity
. In view of the association between AP-1 activity and hemopoietic dif
ferentiation, we suggest that these properties of PML-RARalpha could c
ontribute to the leukemic phenotype and its response to RA.