[Frontiers in Bioscience 14, 497-509, January 1, 2009]

Perspectives in PML: a unifying framework for PML function

Katherine L.B. Borden, Biljana Culjkovic

Institute for Research in Immunology and Cancer and Department of Pathology and Cell Biology, Universite de Montreal, Montreal, Quebec, H4M 1J6 Canada

TABLE OF CONTENTS

1. Abstract
2. Introduction
2.1. Brief overview of PML and PML nuclear bodies
2.2. Scope of this review
3. PML's role in post-transcriptional regulation
3.1. General features
3.2. Network level control of growth promoting genes by PML: modulation of the eIF4E RNA regulon
3.3. What is an RNA regulon?
3.3.1. Example 1: The PML-p53-Mdm2-eIF4E axis
3.3.2. Example 2: The PML-Akt connection and PML induced apoptosis
3.3.3. Example 3: PML mediated growth suppression and transformation suppression
3.3.4. Example 4:PML and suppression of metastatic disease
3.4. Why isn't the eIF4E regulon disrupted in PML-/- mice?
3.4.1. So how would the eIF4E RNA regulon be regulated in the absence of PML?
4. Nuclear PML and PML NBs
4.1. The physical function of PML NB
4.2. Functional PML: bodies or free protein?
5. Cytoplasmic Functions for PML
6. Conclusions and Perspectives
7. Acknowledgments
8. References

1. ABSTRACT

The promyeloctyic leukemia protein (PML) has established activities as a potent repressor of proliferation, and oncogenic transformation, a promoter of apoptosis, an inducer of senescence, and may act as an inhibitor of angiogenesis in mammalian systems. Loss of PML or its nuclear bodies is associated with many human disease states. At the molecular level, the PML protein, and its associated nuclear bodies, play roles in diverse events ranging from mRNA export to DNA repair. PML expression impacts on Akt survival signaling, p53/Mdm2 activity, and cell cycle progression, to name a few. However, there is no discrete set of molecular activities associated with the PML protein that underlie its biochemical and physiological effects. In this review, we postulate a possible molecular model of PML function that could provide a unifying underpinning for many of its disparate activities. In particular, we explore how the ability of PML to coordinately and combinatorially regulate gene expression post-transcriptionally, enables PML to have such broad ranging effects on cellular physiology.