Loss of the Tumor Suppressor PML in Human Cancers of Multiple Histologic Origins

Gurrieri, Carmela; Capodieci, Paola; Bernardi, Rosa; Scaglioni, Pier Paolo; Nafa, Khédoudja; Rush, Laura J.; Verbel, David; Cordon‐Cardo, Carlos; Pandolfi, Pier Paolo

doi:10.1093/jnci/djh043

Cited by 310 publications

(381 citation statements)

References 31 publications

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“…As PML expression is frequently deregulated in human tumour cell lines and/ or during oncogenesis Gurrieri et al, 2004;Scaglioni et al, 2006), we analysed several human tumour and pseudoprimary cell lines for endogenous PML expression (Supplementary Figure 1). Consequently, we decided to use human hepatocytic cells (HepaRG) (Gripon et al, 2002;Cerec et al, 2007), as they express PML in the well-defined physiological amounts (Condemine et al, 2006) and represent a suitable system to analyse endogenously PML components during viral infection Lukashchuk and Everett, 2010).…”

Section: Sumoylation Of E1b-55k Regulates Pml Interaction P Wimmer Et Almentioning

confidence: 99%

“…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.…”

Section: Introductionmentioning

confidence: 99%

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

Wimmer

Schreiner

Everett³

et al. 2010

Oncogene

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The E1B-55K product from human adenovirus is a substrate of the small ubiquitin-related modifier (SUMO)-conjugation system. SUMOylation of E1B-55K is required to transform primary mammalian cells in cooperation with adenovirus E1A and to repress p53 tumour suppressor functions. The biochemical consequences of SUMO1 conjugation of 55K have so far remained elusive. Here, we report that E1B-55K physically interacts with different isoforms of the tumour suppressor protein promyelocytic leukaemia (PML). We show that E1B-55K binds to PML isoforms IV and V in a SUMO1-dependent and -independent manner. Interaction with PML-IV promotes the localization of 55K to PMLcontaining subnuclear structures (PML-NBs). In virusinfected cells, this process is negatively regulated by other viral proteins, indicating that binding to PML is controlled through reversible SUMOylation in a timely coordinated manner. These results together with earlier work are consistent with the idea that SUMOylation regulates targeting of E1B-55K to PML-NBs, known to control transcriptional regulation, tumour suppression, DNA repair and apoptosis. Furthermore, they suggest that SUMO1-dependent modulation of p53-dependent growth suppression through E1B-55K PML-IV interaction has a key role in adenovirus-mediated cell transformation.

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Section: Sumoylation Of E1b-55k Regulates Pml Interaction P Wimmer Et Almentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Wimmer

Schreiner

Everett³

et al. 2010

Oncogene

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“…PML-knockout mice develop tumors upon exposure to carcinogens (Wang et al, 1998) and enhance tumorigenesis in mice with partial loss of PTEN (Trotman et al, 2006). Furthermore, a partial or complete loss of PML has been observed in multiple human cancers, including colon and prostate adenocarcinomas, breast and lung carcinomas, lymphomas, Central Nervous System tumors and germ cell tumors (Gurrieri et al, 2004). The percentage of deregulated PML expression in certain cancers (for example, prostate) has been reported to reach 60-70%.…”

Section: Pml Regulates the Phosphorylation Of P53 By Ck1mentioning

confidence: 99%

PML enhances the regulation of p53 by CK1 in response to DNA damage

et al. 2008

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In response to stress, p53 is accumulated and activated to induce appropriate growth inhibitory responses. This requires the release of p53 from the constraints of its negative regulators Mdm2 and Mdm4. A key event in this dissociation is the phosphorylation of p53 at threonine residue (Thr18) within the Mdm2/4-binding domain. Casein kinase 1 (CK1) plays a major role in this phosphorylation. The promyelocytic leukemia protein (PML) regulates certain modifications of p53 in response to DNA damage. Here, we investigated the role of PML in the regulation of Thr18 phosphorylation. We found that PML enhances Thr18 phosphorylation of endogenous p53 in response to stress. On DNA damage, CK1 accumulates in the cell, with a proportion concentrated in the nucleus together with p53 and PML. Furthermore, CK1 interacts with endogenous p53 and PML, and this interaction is enhanced by genotoxic stress. Inhibition of CK1 impairs the protection of p53 by PML from Mdm2-mediated degradation. Our findings support a role for PML in the regulation of p53 by CK1. We propose that following DNA damage, PML facilitates Thr18 phosphorylation by recruiting p53 and CK1 into PML nuclear bodies, thereby protecting p53 from inhibition by Mdm2, leading to p53 activation.

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“…PML-RARa contributes to acute promyelocytic leukemia (APL) 2,3 and downregulation of PML was observed in multiple human cancers. 4 PML knockout (KO) mice are resistant to lethal doses of ionizing irradiation (IR), and exhibit genomic instability and enhanced susceptibility to tumorigenesis upon exposure to carcinogens 1,5 or in the context of additional oncogenic events (e.g., a loss of Pten 6 ). The myriad of PML functions have been linked to its function in PML nuclear body (PML-NB) formation.…”

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confidence: 99%

E6AP promotes the degradation of the PML tumor suppressor

et al. 2009

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The promyelocytic leukemia (PML) tumor suppressor is essential for the formation of PML nuclear bodies (NBs). PML and PMLNBs have been implicated in the regulation of growth inhibition, senescence and apoptosis. PML is activated in response to stress signals and is downregulated in certain human cancers. However, the factors mediating PML stability are incompletely understood. Here we demonstrate that a catalytically active form of the mammalian E3 ligase E6AP (HPV E6-associated protein) acts to reduce the half-life of the PML protein by promoting its degradation in the proteasome. E6AP mediates the ubiquitination of PML in an in vitro ubiquitination assay. E6AP and PML interact at physiological levels and colocalize in PML-NBs. Importantly, PML protein expression is elevated in multiple organs and cell types from E6AP null mice and in lymphoid cells is associated with increased number and intensity of PML-NBs. This PML elevation is enhanced in response to DNA damage. Our results identify E6AP as an important regulator of PML and PML-NBs. The promyelocytic leukemia (PML) tumor suppressor is implicated in the regulation of cell-cycle progression, premature senescence (triggered by oncogenic Ras) and apoptosis (reviewed by Bernardi and Pandolfi 1 ). Deregulation of PML can be oncogenic. PML-RARa contributes to acute promyelocytic leukemia (APL) 2,3 and downregulation of PML was observed in multiple human cancers. 4 PML knockout (KO) mice are resistant to lethal doses of ionizing irradiation (IR), and exhibit genomic instability and enhanced susceptibility to tumorigenesis upon exposure to carcinogens 1,5 or in the context of additional oncogenic events (e.g., a loss of Pten 6 ). The myriad of PML functions have been linked to its function in PML nuclear body (PML-NB) formation. 7 These are dynamic structures whose configuration and composition are modified in response to specific stress signals. 8 However, their mechanisms of action are only partially understood and are believed to be mediated by key proteins that are recruited to these structures, including pRb, SUMO, Daxx and p53. 9 The regulation of certain proteins, such as p53, is associated with the PML-NBs. 9 Stress stimuli that have been identified as activators of PML and PML-NBs include interferon (a and g), DNA damage, oncogenic stress and viral infection (reviewed in references 1,8,10 ). In contrast, exposure of cells to arsenic trioxide (As 2 O 3 ) or retinoic acid promotes PML degradation. 11 In contrast, the overexpression of specific cellular ubiquitin ligases, such as the Siah protein, 12 or certain viral ubiquitin ligases, such as the ICP0 regulatory protein of herpesvirus-1, 10 promotes the proteasomal degradation of PML and PML-RARa. However, the nature of the underlying mechanism of this degradation and whether it occurs under physiological conditions is not known. Recently, a function for CK2-mediated phosphorylation of PML (on serine 517) in the control of its protein stability was demonstrated. 13 In addition to phosphorylation, the covalen...

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Loss of the Tumor Suppressor PML in Human Cancers of Multiple Histologic Origins

Abstract: PML protein expression is frequently lost in human cancers of various histologic origins, and its loss associates with tumor grade and progression in some tumor histotypes.

Cited by 310 publications

References 31 publications

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

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

PML enhances the regulation of p53 by CK1 in response to DNA damage

E6AP promotes the degradation of the PML tumor suppressor

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