The function, regulation and therapeutic implications of the tumor suppressor protein, PML

Abstract

The tumor suppressor protein, promyelocytic leukemia protein (PML), was originally identified in acute promyelocytic leukemia due to a chromosomal translocation between chromosomes 15 and 17. PML is the core component of subnuclear structures called PML nuclear bodies (PML-NBs), which are disrupted in acute promyelocytic leukemia cells. PML plays important roles in cell cycle regulation, survival and apoptosis, and inactivation or down-regulation of PML is frequently found in cancer cells. More than 120 proteins have been experimentally identified to physically associate with PML, and most of them either transiently or constitutively co-localize with PML-NBs. These interactions are associated with many cellular processes, including cell cycle arrest, apoptosis, senescence, transcriptional regulation, DNA repair and intermediary metabolism. Importantly, PML inactivation in cancer cells can occur at the transcriptional-, translational- or post-translational- levels. However, only a few somatic mutations have been found in cancer cells. A better understanding of its regulation and its role in tumor suppression will provide potential therapeutic opportunities. In this review, we discuss the role of PML in multiple tumor suppression pathways and summarize the players and stimuli that control PML protein expression or subcellular distribution.

Keywords: PML; PML nuclear bodies; Therapy; Tumor suppressor protein.

Fig. 1

Summary of PML functions in diseases. PML plays pivotal roles in the indicated conditions including anti-inflammatory responses, metabolism, stem cell maintenance, circadian rhythms, aging and unfolded protein responses. PML protein exerts its tumor suppressive function by regulating the cell cycle, apoptosis, senescence, migration, angiogenesis, and DNA repair pathways

Fig. 2

A schematic diagram of PML functional domains. All PML isoforms share the same N-terminal 418 amino acids, which contain RING (R), B-Box1 (B1), B-Box1 (B2) and coiled coil (CC) domains. Nuclear PML isoforms share the same N-terminal 552 amino acids, which in addition to RBCC, contains a nuclear localization signal (NLS) and a SUMO-interacting motif (SIM) (66) present in PML isoforms I–V. Only PMLI contains a putative nuclear export signal (NES) at its C-terminus

Fig. 3

PML interactome. Based on the data from BIOGRID (http://www.thebiogrid.org/), 120 proteins transiently or constitutively physically interact with PML. This has been demonstrated by affinity capture followed by Western blotting experiments. The PML-associating proteins identified by high-throughput methods are not included. The thicker of the line the more publications support the association

Fig. 4

PML NB-mediated tumor suppression pathways. PML NBs repress protein function by sequestration, mediating protein–protein interaction, or acting as a post-translational modification hub to regulate diverse tumor suppressor pathways