Role of the promyelocytic leukaemia protein in cell death regulation

Samantha Dickson Brain Cancer Unit, UCL Cancer Institute, 72 Huntley Street, London WC1E 6BT, UK.
Cell Death & Disease (Impact Factor: 5.01). 01/2012; 3(1):e247. DOI: 10.1038/cddis.2011.122
Source: PubMed


The promyelocytic leukaemia gene PML was originally identified at the t(15;17) translocation of acute promyelocytic leukaemia, which generates the oncogene PML-retinoic acid receptor a. PML epitomises a subnuclear structure called PML nuclear body. Current models propose that PML through its scaffold properties is able to control cell growth and survival at many different levels. Here we discuss the current literature and propose new avenues for investigation. Cell Death and Disease (2012) 3, e247; doi:10.1038/cddis.2011.122; published online 12 January 2012

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    • "Translocation involving the PML locus (15q22) resulting in the expression of a fusion protein PML-RARα is found in the majority of acute promyelocytic leukemia cases [49]. Moreover, a partial or complete loss of the PML protein expression has been observed in several solid tumors [48], highlighting its role in cancerogenesis. In this study the A allele of PML_rs9479 G > A enhanced binding of miR-510-5p resulting in 19% decrease in the protein expression as compared to the G allele. "
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    ABSTRACT: Background MicroRNA dysregulation is a common event in leukemia. Polymorphisms in microRNA-binding sites (miRSNPs) in target genes may alter the strength of microRNA interaction with target transcripts thereby affecting protein levels. In this study we aimed at identifying miRSNPs associated with leukemia risk and assessing impact of these miRSNPs on miRNA binding to target transcripts. Methods We analyzed with specialized algorithms the 3′ untranslated regions of 137 leukemia-associated genes and identified 111 putative miRSNPs, of which 10 were chosen for further investigation. We genotyped patients with acute myeloid leukemia (AML, n = 87), chronic myeloid leukemia (CML, n = 140), childhood acute lymphoblastic leukemia (ALL, n = 101) and healthy controls (n = 471). Association between SNPs and leukemia risk was calculated by estimating odds ratios in the multivariate logistic regression analysis. For miRSNPs that were associated with leukemia risk we performed luciferase reporter assays to examine whether they influence miRNA binding. Results Here we show that variant alleles of TLX1_rs2742038 and ETV6_rs1573613 were associated with increased risk of childhood ALL (OR (95% CI) = 3.97 (1.43-11.02) and 1.9 (1.16-3.11), respectively), while PML_rs9479 was associated with decreased ALL risk (OR = 0.55 (0.36-0.86). In adult myeloid leukemias we found significant associations between the variant allele of PML_rs9479 and decreased AML risk (OR = 0.61 (0.38-0.97), and between variant alleles of IRF8_ rs10514611 and ARHGAP26_rs187729 and increased CML risk (OR = 2.4 (1.12-5.15) and 1.63 (1.07-2.47), respectively). Moreover, we observed a significant trend for an increasing ALL and CML risk with the growing number of risk genotypes with OR = 13.91 (4.38-44.11) for carriers of ≥3 risk genotypes in ALL and OR = 4.9 (1.27-18.85) for carriers of 2 risk genotypes in CML. Luciferase reporter assays revealed that the C allele of ARHGAP26_rs187729 creates an illegitimate binding site for miR-18a-3p, while the A allele of PML_rs9479 enhances binding of miR-510-5p and the C allele of ETV6_rs1573613 weakens binding of miR-34c-5p and miR-449b-5p. Conclusions Our study implicates that microRNA-binding site polymorphisms modulate leukemia risk by interfering with the miRNA-mediated regulation. Our findings underscore the significance of variability in 3′ untranslated regions in leukemia.
    Full-text · Article · Jun 2014 · Journal of Hematology & Oncology
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    • "IKKβ-catalyzed phosphorylation of TATP63 inhibits its transcriptional activity by impairing the association with p300 [Liao et al., 2013]. A central regulator of all the TP53 family members is the promyelocytic leukemia protein (PML) [Salomoni et al., 2012] that recruits TP53, TP63, and TP73 to nuclear subdomains, named PML–nuclear bodies (NBs) [Guo et al., 2000; Bernassola et al., 2004; Bernassola et al., 2005]. Within these domains, PML facilitates the association of the TP53 proteins with common regulators and transcriptional coactivators, including HIPK2, YAP1, p300, and DAXX [Kim et al., 2003; Bernassola et al., 2004; Lapi et al., 2008]. "
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    ABSTRACT: In mammals, the p53 family comprises two additional members, p63 and p73 (hereafter referred to as TP53, TP63 and TP73, respectively). The usage of two alternative promoters produces protein variants either with (TA isoforms) or without (ΔN isoforms) the N-terminal transactivation domain. In general, the TA proteins exert TP53-like tumor suppressive activities through their ability to activate a common set of target genes. The ΔN proteins can act as dominant negative inhibitors of the transcriptionally active family members. Additionally, they possess intrinsic specific biological activities due to the presence of alternative transactivation domains, and as a result of engaging a different set of regulators. This review summarizes the current understanding of upstream regulators and downstream effectors of the TP53 family proteins, with particular emphasis on those, which are relevant for their role in tumorigenesis. Furthermore, we highlight the existence of networks and cross-talks amongst the TP53 family members, their modulators as well as the transcriptional targets. This article is protected by copyright. All rights reserved.
    Preview · Article · Jun 2014 · Human Mutation
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    • "A well-defined downstream effector pathway of PML (Salomoni et al., 2008, 2012) involves the key tumor suppressor p53. In response to stress, PML promotes the activation and stabilization of p53 by protecting it from its major inhibitor Mdm2, and facilitating key post-translational modifications (Louria-Hayon et al., 2003; Bernardi et al., 2004; Alsheich-Bartok et al., 2008). "
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    ABSTRACT: The tumor suppressor function of the promyelocytic leukemia (PML) protein was first identified as a result of its dysregulation in acute promyelocytic leukemia, however, its importance is now emerging far beyond hematological neoplasms, to an extensive range of malignancies, including solid tumors. In response to stress signals, PML coordinates the regulation of numerous proteins, which activate fundamental cellular processes that suppress tumorigenesis. Importantly, PML itself is the subject of specific post-translational modifications, including ubiquitination, phosphorylation, acetylation, and SUMOylation, which in turn control PML activity and stability and ultimately dictate cellular fate. Improved understanding of the regulation of this key tumor suppressor is uncovering potential opportunities for therapeutic intervention. Targeting the key negative regulators of PML in cancer cells such as casein kinase 2, big MAP kinase 1, and E6-associated protein, with specific inhibitors that are becoming available, provides unique and exciting avenues for restoring tumor suppression through the induction of apoptosis and senescence. These approaches could be combined with DNA damaging drugs and cytokines that are known to activate PML. Depending on the cellular context, reactivation or enhancement of tumor suppressive PML functions, or targeted elimination of aberrantly functioning PML, may provide clinical benefit.
    Full-text · Article · May 2013 · Frontiers in Oncology
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