THE PROMYELOCYTIC LEUKEMIA GENE-PRODUCT (PML) FORMS STABLE COMPLEXES WITH THE RETINOBLASTOMA PROTEIN

PML is a nuclear protein with growth-suppressive properties originally identified in the context of the PML-retinoic acid receptor alpha (RA R alpha) fusion protein of acute promyelocytic leukemia. PML localizes within distinct nuclear structures, called nuclear bodies, which are disrupted by the expression of PML-RAR alpha. We report that PML coloc alizes with the nonphosphorylated fraction of the retinoblastoma prote in (pRB) within nuclear bodies and that PRE is delocalized by PML-RAR alpha expression. Both PML and PML-RAR alpha form complexes with the n onphosphorylated form of pRB in vivo, and they interact with the pocke t region of pRB. The regions of PML and PML-RAR alpha involved in pRB binding differ; in fact, the B boxes and the C-terminal region of PML, the latter of which is not present in PML-RAR alpha, are essential fo r the formation of stable complexes with pRB. Functionally, PML abolis hes activation of glucocorticoid receptor-regulated transcription by p RB, whereas PML-RAR alpha further increases it. Our results suggest th at PML may be part of transcription-regulatory complexes and that the oncogenic potential of the PML-RAR alpha protein may derive from the a lteration of PML-regulated transcription.