The Role of PML in Tumor Suppression

Abstract

The PML gene, involved in the t(15;17) chromosomal translocation of acute promyelocytic leukemia (APL), encodes a protein which localizes to the PML-nuclear body, a subnuclear macromolecular structure. PML controls apoptosis, cell proliferation, and senescence. Here, we review the current understanding of its role in tumor suppression.

PML4 induces differentiation by Myc destabilization

“…Moreover, different PML isoforms might act in parallel on Myc in different pathways and/or promoters. Analyzing the exact expression profile of PML isoforms in different cell types might provide important clues on how PML can contribute to the large number of different and in part tissue-specific functions that were reported (Salomoni and Pandolfi, 2002;Strudwick and Borden, 2002).…”

“…The PML protein is the scaffolding component of subnuclear compartments called PML nuclear bodies (NBs, also designated PML oncogenic domain or nuclear domain 10). PML NBs have been shown to play a role in a still increasing number of cellular functions including growth suppression, genomic stability, apoptosis, DNA repair, as well as transcriptional response to interferon (Salomoni and Pandolfi, 2002;Strudwick and Borden, 2002). Taking these functions into account, it is not surprising that PML has a tumor suppressive role, and its alteration is implicated in cancer pathogenesis, including leukemia (Salomoni and Pandolfi, 2002).…”

Remodeling of chromatin structure in senescent cells and its potential impact on tumor suppression and aging

“…However, in cells approaching senescence, regardless of whether the trigger is an activated oncogene, short telomeres or cell stress, HIRA is translocated into a specific subnuclear organelle, the PML nuclear body. Most human cells contain 20-30 PML nuclear bodies, which are typically 0.1-1μM in diameter and enriched in the protein PML, as well as many other nuclear regulatory proteins (14,107). PML bodies have been previously implicated in various cellular processes, including tumor suppression and cellular senescence (34,42,94).…”

SUMO modification of E1B-55K oncoprotein regulates isoform-specific binding to the tumour suppressor protein PML

“…The PML protein has first been described as the causal agent in acute promyelocytic leukaemia as a fusion with the RARa receptor generated by the chromosomal translocation t(15;17) (Ascoli and Maul, 1991;de The et al, 1991;Kakizuka et al, 1991;Chang et al, 1992;Goddard et al, 1992;Kastner et al, 1992;Pandolfi et al, 1992;Dyck et al, 1994;Koken et al, 1994;Weis et al, 1994;Melnick and Licht, 1999;. Since these initial findings, it has become evident that PML is a general tumour suppressor frequently deregulated in various tumour types (Gurrieri et al, 2004) most presumably involving secondary effects of PML bodies as sites of protein degradation (Lallemand-Breitenbach et al, 2001), transcriptional regulation (Li et al, 2000;Zhong et al, 2000), cellular senescence (Ferbeyre et al, 2000;Pearson et al, 2000;Bischof et al, 2002;Langley et al, 2002), tumour suppression (Salomoni and Pandolfi, 2002;Salomoni et al, 2008), DNA repair (Bischof et al, 2001;Carbone et al, 2002), apoptosis (Hofmann and Will, 2003;Takahashi et al, 2004) and epigenetic regulation (Torok et al, 2009). Interestingly, functional inactivation of the E1B-55K leucine-rich nuclear export sequence (NES) induces enhanced posttranslational modification of E1B-55K by the small ubiquitin-related modifier 1 (SUMO1) at lysine 104 (SUMO-conjugation motif, SCM) as well as augments transformation of primary rat cells involving the accumulation of p53, E1B-55K and PML in subnuclear aggregates (Endter et al, 2001(Endter et al, , 2005.…”