A fusion between the promyelocytic leukemia (PML) protein and the retinoic
acid receptor-alpha (RAR alpha) results in the transforming protein of acut
e promyelocytic leukemia, PMM-RAR alpha. PML has growth-suppressive propert
ies and is localized within distinct nuclear structures referred to as nucl
ear bodies. PML participates in numerous cellular functions, including tran
scriptional activation, apoptosis, and transcriptional repression, whereas
PMM-RAR alpha blocks these functions. However, the role played by PMM-RAR a
lpha in leukemogenesis remains unclear. Here we report that PML is required
for transcriptional repression mediated by the tumor suppressor Rb. Rb int
eracts with the histone decaetylase (HDAC) complex containing co-repressors
and represses the transcription of the E2F target genes. Overexpression of
PAM enhanced Rb-mediated repression. The degree of Rb-mediated repression
was weakened by injecting antiPML antibodies and was lower in PML-deficient
mouse embryonic fibroblasts. PAM-RAR alpha inhibited Rb-mediated repressio
n, and two co-repressor-interacting sites on the PML-RAR alpha molecule wer
e required for this activity. Furthermore, PMM-RAR alpha blocked the intera
ction between Rb and HDAC. Thus, aberrant binding of PML-RAR alpha to co-re
pressor-HDAC complexes may inhibit their association with Rb, resulting in
the abrogation of Rb activity. Thus, the disruption of Rb-mediated repressi
on may be a contributory factor in leukemogenesis.