MODULATION OF FOS-MEDIATED AP-1 TRANSCRIPTION BY THE PROMYELOCYTIC LEUKEMIA PROTEIN

The growth and transformation suppressor function of promyelocytic leu kemia (PML) protein are disrupted in acute promyelocytic leukemia (APL ) as a result of its fusion to the RAR alpha gene by t(15;17) transloc ation. There is significant sequence homology between the dimerization domain of PML and the Fos family of proteins, which imply that PML ma y be involved in AP-1 activity. Here we show that PML can cooperate wi th Fos to stimulate its AP-1-mediated transcriptional activity. Cotran sfection of PML with GAL4/Fos strongly induced Fos-mediated activation of GAL4-responsive reporters, indicating a functional interaction bet ween Fos and PML in vivo. Deletion analysis of Fos and PML demonstrate d that the intact C-terminal domain of Fos (containing the dimerizatio n domain), and the RING-finger, B1 box and nuclear localization domain s of PML are involved in the cooperative activity of Fos and PML. Immu noprecipitation and electrophoretic mobility shift assay showed that P ML is associated with the AP-1 complex. PMLRAR alpha was also found to enhance the transcriptional activity of GAL4/Fos. The addition of ret inoic acid abrogated the PMLRAR alpha, but not PML-induced stimulation of GAL4/Fos activity in a dose-dependent manner. This study demonstra ted that PML is involved in the AP-1 complex and can modulate Fos-medi ated transcriptional activity, which may contribute to its growth supp ressor function.