Role of PML in Cell Growth and the Retinoic Acid Pathway

Wang, Zhu Gang; Delva, Laurent; Gáboli, Mirella; Rivi, Roberta; Giorgio, Marco; Cordon‐Cardo, Carlos; Grosveld, Frank; Pandolfi, Pier Paolo

doi:10.1126/science.279.5356.1547

Cited by 466 publications

(101 citation statements)

References 25 publications

(9 reference statements)

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“…3 Overexpression of PML inhibits cell proliferation, 4 whereas pml −/− cells grow faster than their wild-type counterparts. 5 Moreover, pml −/− cells are resistant to multiple apoptotic stimuli, for example, hydrogen peroxide (H 2 O 2 ), tumor necrosis factor- α , and ionizing radiation. 6 There are multiple PML spliced isoforms.…”

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confidence: 99%

Deacetylation of the tumor suppressor protein PML regulates hydrogen peroxide-induced cell death

et al. 2014

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The promyelocytic leukemia protein (PML) is a tumor suppressor that is expressed at a low level in various cancers. Although post-translational modifications including SUMOylation, phosphorylation, and ubiquitination have been found to regulate the stability or activity of PML, little is known about the role of its acetylation in the control of cell survival. Here we demonstrate that acetylation of lysine 487 (K487) and SUMO1 conjugation of K490 at PML protein are mutually exclusive. We found that hydrogen peroxide (H2O2) promotes PML deacetylation and identified SIRT1 and SIRT5 as PML deacetylases. Both SIRT1 and SIRT5 are required for H2O2-mediated deacetylation of PML and accumulation of nuclear PML protein in HeLa cells. Knockdown of SIRT1 reduces the number of H2O2-induced PML-nuclear bodies (NBs) and increases the survival of HeLa cells. Ectopic expression of wild-type PML but not the K487R mutant rescues H2O2-induced cell death in SIRT1 knockdown cells. Furthermore, ectopic expression of wild-type SIRT5 but not a catalytic defective mutant can also restore H2O2-induced cell death in SIRT1 knockdown cells. Taken together, our findings reveal a novel regulatory mechanism in which SIRT1/SIRT5-mediated PML deacetylation plays a role in the regulation of cancer cell survival.

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confidence: 99%

Deacetylation of the tumor suppressor protein PML regulates hydrogen peroxide-induced cell death

et al. 2014

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“…We hypothesize that cellular intersections connecting different pathways may serve as molecular platforms for ICP0 to effectively coordinate its multiple functions. A dynamic nuclear structure, nuclear domain 10 (ND10), which has been implicated in numerous cellular processes, including gene regulation (21,22), apoptosis (23,24), DNA repair (25), oncogenesis (26,27), and antiviral defense (28), is a suitable candidate to bridge the cross talk and networking among different cell pathways.…”

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confidence: 99%

Identification of Three Redundant Segments Responsible for Herpes Simplex Virus 1 ICP0 To Fuse with ND10 Nuclear Bodies

Zheng

2015

J Virol

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Infected cell protein 0 (ICP0) of herpes simplex virus 1 (HSV-1) is a key regulator in both lytic and latent infections. In lytic infection, an important early event is the colocalization of ICP0 to nuclear domain 10 (ND10), the discrete nuclear bodies that impose restrictions on viral expression. ICP0 contains an E3 ubiquitin ligase that degrades promyelocytic leukemia protein (PML) and Sp100, two major components of ND10, and disperses ND10 to alleviate repression. We previously reported that the association between ICP0 and ND10 is a dynamic process that includes three steps: adhesion, fusion, and retention. ICP0 residues 245 to 474, defined as ND10 entry signal (ND10-ES), is a region required for the fusion step. Without ND10-ES, ICP0 adheres at the ND10 surface but fails to enter. In the present study, we focus on characterizing ND10-ES. Here we report the following. IMPORTANCE ND10 nuclear bodies are part of the cell-intrinsic antiviral defenses that restrict viral gene expression upon virus infection. As a countermeasure, infected cell protein 0 (ICP0) of herpes simplex virus 1 (HSV-1) localizes to ND10s, degrades the ND10 organizer, and disperses ND10 components in order to alleviate repression. We studied the ICP0-ND10 association to delineate elements important for this dynamic interaction and to understand its role in viral replication and host defense. In this work, we show that ICP0 contains three redundant segments to ensure an effective mergence of ICP0 with ND10 nuclear bodies. This is the first study to systematically investigate ICP0 elements that are important for ICP0-ND10 fusion. Herpes simplex virus 1 (HSV-1) infected cell protein 0 (ICP0) is a multifunctional immediate early protein that plays a key role in both lytic and latent infections. The protein is essential at a low multiplicity of infection (MOI) in cultured cells (1). Its main functions are to counteract cell-intrinsic and innate defenses by targeting saturable cellular restrictive factors and consequently to enhance viral gene expression (1).The 775-amino-acid ICP0 contains a RING (really interesting new gene) type E3 ubiquitin ligase in its second exon (2, 3), which ubiquitinates various cellular proteins for proteasomal degradation. Known ICP0 substrates include promyelocytic leukemia protein (PML) (4), speckled protein Sp100 (4), DNA-dependent protein kinase (DNA-PK) (5), centromeric protein A (CENP-A) (6), and interferon (IFN)-inducible protein 16 (IFI16) (7). Some of these ICP0 substrates are restrictive for HSV-1 infection, inasmuch as small interfering RNA (siRNA) knockdown of PML, Sp100, or IFI16, individually or in combination, enhances viral replication in the absence of ICP0 (8, 9).A second tactic of ICP0 to overcome antiviral defenses is to regulate a diverse array of cell pathways via protein-protein interactions. For example, ICP0 interacts with corepressor of RE1-silencing transcription factor (CoREST). This interaction leads to the dissociation of histone deacetylases (HDACs) 1 and 2 from the REST/CoREST...

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“…HDACs are one such potential candidate, as they have been shown to interact with both pRB and PML. 36,37 We don't favor this interpretation, because our previous studies have indicated that HDACcontaining complexes interact with pRB in a GST-RB pull-down assay irrespective of the growth state of the cells. 29 Based on this line of reasoning, we expect that PML-pRB interactions are likely quite direct.…”

Section: Discussionmentioning

confidence: 92%

“…33,34 Indeed, Pml −/− mice show increased susceptibility to cancer-promoting agents. 35,36 Interestingly, in a recent study by Vernier et al the authors showed that expression of PML in U2OS osteosarcoma cells results in the association of PML with E2F target genes and repression of their expression. 23 However, other studies have suggested that the formation of PML nuclear bodies is dispensable for induction of senescence, and that the individual PML proteins are key.…”

Section: Discussionmentioning

confidence: 99%

The retinoblastoma protein and PML collaborate to organize heterochromatin and silence E2F-responsive genes during senescence

Talluri

Dick

2013

Cell Cycle

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Role of PML in Cell Growth and the Retinoic Acid Pathway

Cited by 466 publications

References 25 publications

Deacetylation of the tumor suppressor protein PML regulates hydrogen peroxide-induced cell death

Deacetylation of the tumor suppressor protein PML regulates hydrogen peroxide-induced cell death

Identification of Three Redundant Segments Responsible for Herpes Simplex Virus 1 ICP0 To Fuse with ND10 Nuclear Bodies

The retinoblastoma protein and PML collaborate to organize heterochromatin and silence E2F-responsive genes during senescence

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