Effect of PML and PML-RAR on the transactivation properties and subcellular distribution of steroid hormone receptors.

Abstract

PML (promyelocytic leukemia) is a protein involved in the t (15;17) translocation of promyelocytic leukemia and is mainly localized in nuclear bodies. Here we show that PML exerts a very powerful enhancing activity (up to 20-fold) on the transactivating properties of the progesterone receptor (PR) and has a similar effect on several other steroid hormone receptors. There is probably a direct or indirect interaction between PR and PML, because when the latter was expressed at high concentrations it shifted PR into the nuclear bodies. The use of deletion mutants showed that both activation functions (AF1 and AF2) of PR as well as the coiled coil and His-Cys-rich domains of PML were required for transcriptional enhancement. The fusion protein PML-RAR which is not localized in nuclear bodies, also enhanced the transactivating activity of PR, but this effect was totally suppressed by the administration of retinoic acid. PML, which is ubiquitously expressed, may thus be involved in the transactivation properties of steroid hormone receptors. This mechanism may also play a role in the oncogenic properties of PML-RAR and in their suppression by retinoic acid.

Expression and role of PML gene in normal adult hematopoiesis: functional interaction between PML and Rb proteins in erythropoiesis

“…This rearrangement is much more frequently observed as compared with other known APL fusionproteins, PLZF/RARa (Chen et al, 1993), NPM/ RARa (Redner et al, 1996) and NuMA-RARa (Wells et al, 1997) reported in M3 leukemias. In addition, PML possesses structural and functional features of a transcription factor (Kastner et al, 1992;Guiochon-Mantel et al, 1995), and biological activity of a growth regulator (Mu et al, 1994). PML mRNA and protein expression is low in quiescent HPCs and is induced by growth factor stimulation of Figure 6 E ect on BFU-E colony formation upon HPCs treatment with appropriate concentrations of (i) antisense (AS) oligomer to PML (a1-PML), (ii) antisense oligomer to Rb (a-Rb), (iii) scrambled a1-PML (Scr a1-PML) and/or (iv) scrambled a-Rb (Scr aRb), added alone or in combination as indicated at day 5 of culture.…”

“…PML has been regarded as a growth regulator (Mu et al, 1994;Liu et al, 1995;He et al, 1997a;Guiochon-Mantel et al, 1995). Indeed, when overexpressed, it suppresses: (i) anchorage-independent growth of APL-derived NB4 cells (Mu et al, 1994); (ii) oncogenic transformation of rat embryonic ®broblasts by cooperative oncogenes and of NIH3T3 cells by activated Neu ; and (iii) growth and tumorigenicity of prostate cancer cells (He et al, 1997a).…”

“…These ®ndings suggest that PML shares many properties with tumor suppressors. The molecular pathway through which PML exerts its function remains unknown, although it has been suggested that PML can act as a transcription coregulator (Guiochon-Mantel et al, 1995).…”

Pathways of retinoic acid- or arsenic trioxide-induced PML/RARα catabolism, role of oncogene degradation in disease remission

“…In that sense, PML NBs were shown to be disorganized during many viral infections. This link between PML bodies and the imunoproteasome could account for a number of apparently contradictory observations, such as the susceptibility of PML7/7 mice to infections or the frequent colocalisation of PML and overexpressed/misfolded proteins (Fabunmi et al, 2001;Guiochon-Mantel et al, 1995;Skinner et al, 1997;Wang et al, 1998a).…”

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).…”