PML-RARα alleviates the transcriptional repression mediated by tumor suppressor Rb

A fusion between the promyelocytic leukemia (PML) protein and the retinoic acid receptor-alpha (RAR alpha) results in the transforming protein of acute promyelocytic leukemia, PMM-RAR alpha. PML has growth-suppressive properties and is localized within distinct nuclear structures referred to as nuclear bodies. PML participates in numerous cellular functions, including transcriptional activation, apoptosis, and transcriptional repression, whereas PMM-RAR alpha blocks these functions. However, the role played by PMM-RAR alpha in leukemogenesis remains unclear. Here we report that PML is required for transcriptional repression mediated by the tumor suppressor Rb. Rb interacts 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 repression, and two co-repressor-interacting sites on the PML-RAR alpha molecule were required for this activity. Furthermore, PMM-RAR alpha blocked the interaction between Rb and HDAC. Thus, aberrant binding of PML-RAR alpha to co-repressor-HDAC complexes may inhibit their association with Rb, resulting in the abrogation of Rb activity. Thus, the disruption of Rb-mediated repression may be a contributory factor in leukemogenesis.