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Review
. 2018 Jan 25:8:5.
doi: 10.1186/s13578-018-0204-8. eCollection 2018.

PML: Regulation and multifaceted function beyond tumor suppression

Kuo-Sheng Hsu  1   2 , Hung-Ying Kao  1   3
Affiliations
Review

PML: Regulation and multifaceted function beyond tumor suppression

Kuo-Sheng Hsu et al. Cell Biosci. .

Erratum in

Abstract

Promyelocytic leukemia protein (PML) was originally identified as a fusion partner of retinoic acid receptor alpha in acute promyelocytic leukemia patients with the (15;17) chromosomal translocation, giving rise to PML-RARα and RARα-PML fusion proteins. A body of evidence indicated that PML possesses tumor suppressing activity by regulating apoptosis, cell cycle, senescence and DNA damage responses. PML is enriched in discrete nuclear substructures in mammalian cells with 0.2-1 μm diameter in size, referred to as alternately Kremer bodies, nuclear domain 10, PML oncogenic domains or PML nuclear bodies (NBs). Dysregulation of PML NB formation results in altered transcriptional regulation, protein modification, apoptosis and cellular senescence. In addition to PML NBs, PML is also present in nucleoplasm and cytoplasmic compartments, including the endoplasmic reticulum and mitochondria-associated membranes. The role of PML in tumor suppression has been extensively studied but increasing evidence indicates that PML also plays versatile roles in stem cell renewal, metabolism, inflammatory responses, neural function, mammary development and angiogenesis. In this review, we will briefly describe the known PML regulation and function and include new findings.

Keywords: Angiogenesis; Chemotherapy resistance; Gene expression; Inflammatory responses; Mammary development; Metabolism; Neural function; PML; Protein modification; Proteolysis; Stem cell and cancer stem cell renewal.

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Figures

Fig. 1
Fig. 1
Schematic of PML gene and its isoforms and their localizations. a The primary PML transcript contains nine exons and eight introns and is alternatively spliced. The exons are shown as blue boxes. b The primary PML transcript can be alternatively spliced to generate more than 11 isoforms. Only seven PML mRNA isoforms that share exons 1–4 are shown. Note that all nuclear isoforms (I–VI) harbor exons 1–6. Isoforms III and V contain introns colored in grey that are spliced out in other nuclear isoforms. The asterisks mark the regions from partial exons or introns. In this Figure, the localization, the molecular weight of PML protein isoforms and the sizes of the 3′-UTR of each PML isoform are also shown. PML mRNA isoforms harbor unique 3′-UTRs, with a common 140-bp 5′-UTR containing a functional IRES. SIM SUMO interacting motif, NLS nuclear localization sequence, NES nuclear exportation sequence)
Fig. 2
Fig. 2
Overview of PML regulation by multiple stimuli and molecular mechanisms. PML is a stress responsive protein. Upon various extracellular stimuli or DNA damage, as shown in the blue circle, PML is regulated by different mechanisms, from transcription, translation to protein-level regulation, shown in the grey and yellow circle. ISG isgylation, P phosphorylation, Ub ubiquitination, SUMO sumoylation, AC acetylation, cPML cytoplasmic PML, nPML nuclear PML
Fig. 3
Fig. 3
Overview of PML cellular and physiological functions. PML has the ability to form PML NB and interact with more than 170 proteins. Through these interactions, PML has been reported to control various outcomes from gene expression, mRNA translation to protein-level regulation. In a recent study, PML’s enzymatic activity as an E3 sumoylation ligase was validated. Additionally, cytoplasmic PML can regulate calcium transfer, signal transduction and autophagy. All of PML’s known molecular functions are summarized in the green circle. In physiology and pathology, PML was originally found as a tumor suppressor by controlling cell death, cell cycle, angiogenesis and cell migration. In recent studies, PML was also reported as a key player contributing to cancer therapy resistance. Other PML physiological functions in development, immunity and metabolism are also summarized in the grey circle. ALT alternative lengthening of telomeres
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