TRANSCRIPTIONAL REPRESSION BY THE PROMYELOCYTIC LEUKEMIA PROTEIN, PML

Acute promyelocytic leukemia is characterized by the presence of a t(1 5;17) chromosomal translocation which results in the expression of a c himeric gene product, PMLRAR alpha, consisting of an N-terminal-trunca ted retinoic acid receptor-alpha fused to a C-terminal-truncated PML. Several structural features, and regions of homology to known transcri ption factors, suggest that PML may be involved in the regulation of g ene expression. In this study we have analyzed the transcriptional reg ulatory activity of PML using chimeric GAL4/PML constructs and GAL4-re sponsive reporter plasmids. The data presented demonstrate that PML, w hen fused to the DNA-binding domain of GAL4 (GAL4/PML), inhibits trans cription from GAL4-responsive promoters. The magnitude of this repress ion is cell type and promoter dependent, and deletion studies show tha t the putative coiled-coil and part of the serine-rich regions of PML are required for this activity. These regions are also shown to be res ponsible for the repression of transcription activity from the EGFR pr omoter. The data presented also demonstrate that GAL4/PML can recruit PMLRAR alpha resulting in the retinoid-inducible transcriptional activ ation of a GAL4-responsive promoter, a function dependent on the prese nce of the coiled-coil region of PMLRAR alpha. (C) 1997 Academic Press .