A RA-dependent, tumour-growth suppressive transcription complex is the target of the PML-RARα and T18 oncoproteins

Abstract

PML and Tif1a are fused to RARA and Braf, respectively, resulting in the production of PML-RARalpha and Tif1alpha-B-Raf (T18) oncoproteins. Here we show that PML, Tif1alpha and RXRalpha/RARalpha function together in a transcription complex that is dependent on retinoic acid (RA). We found that PML acts as a ligand-dependent coactivator of RXRalpha/RARalpha. PML interacts with Tif1alpha and CBP. In Pml-/- cells, the RA-dependent induction of genes such as RARB2 and the ability of Tif1alpha and CBP to act as transcriptional coactivators on RA are impaired. We show that both PML and Tif1alpha are growth suppressors required for the growth-inhibitory activity of RA. T18, similar to PML-RARalpha, disrupts the RA-dependent activity of this complex in a dominant-negative manner resulting in a growth advantage. Our data define a new pathway for the control of cell growth and tumorigenesis, and provide a new model for the pathogenesis of acute promyelocytic leukaemia (APL).

A role for PML and the nuclear body in genomic stability

“…BLM's localization to the NB implicates the NB in one or more of these processes. In this respect, it is intriguing that PML has been recently found to regulate transcription (Doucas et al, 1999;Zhong et al, 1999). Here we provide evidence for a role of PML and the NB in maintaining genomic stability.…”

The theory of APL

“…PML can act as a ligand-dependent coactivator of RXRa/RARa through its ability to interact with Tif1a and CBP. In PML 7/7 cells, the RA-dependent induction of genes, such as RARb2, and the ability of Tif1a and CBP to act as transcriptional coactivators upon RA are impaired (Zhong et al, 1999a) All together these data demonstate that X and RARa pathways can cross talk ( Figure 2) and that PMLRARa can disrupt the RA-dependent activity of a tumor-growth suppressive transcription complex in a dominant negative manner at multiple levels, resulting in growth advantage and RA unresponsiveness.…”

Transcriptional regulation in acute promyelocytic leukemia

“…Both PML and PML-RARa were shown to potentiate the transactivating functions of AP-1 (Jun/Fos) (Doucas et al, 1993;Vallian et al, 1998b), the steroid receptors (Guiochon-Mantel et al, 1995), and the hematopoietic transcription factor GATA-2 (Tsuzuki et al, 2000). Further investigations have established that PML does not interact directly with either Jun/Fos or steroid receptors but instead targets transcriptional accessory factors such as CBP and nuclear receptor cofactor TIF1a (Doucas et al, 1999;Vallian et al, 1998b;Zhong et al, 1999). CBP is a histone acetyltransferase that functions as a coactivator for diverse transcription factors including CREB, AP-1 (Jun and Fos), nuclear receptors (NR) and p53 (reviewed in Giles et al, 1998;Shikama et al, 1997).…”

“…Doucas et al (1999) demonstrated that CBP is a component of PODs that associates directly with PML and that CBP-dependent transcription is potentiated by co-expression of PML, supporting an activating role of PML in nuclear receptor and AP-1 pathways. Furthermore, Zhong et al (1999) described a cellular coactivator complex composed of PML, TIF1a and CBP that is recruited to RARE, suggesting that PML is a coactivator for RARs. Finally, PML was found to interact directly with tumor suppressor p53 resulting in activation of p53-dependent pathways (Fogal et al, 2000;Guo et al, 2000;Pearson et al, 2000).…”