Stabilization of p53 by p14ARF without relocation of MDM2 to the nucleolus

Llanos, Susana; Clark, Paula A.; Rowe, Janice; Peters, Gordon

doi:10.1038/35074506

Cited by 247 publications

(304 citation statements)

References 36 publications

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“…One of the targets is the gene encoding the p19ARF, which is a key component of the p19ARF-MDM2-p53 network (Zhang et al, 1998;Zhu et al, 1999;Trimarchi and Lees, 2002). Activation of p19ARF inhibits MDM2, a p53 ubiquitin ligase, enhancing p53 stabilization (Momand et al, 1992;Kubbutat et al, 1997;Pomerantz et al, 1998;Stott et al, 1998;Zhang et al, 1998;Haupt et al, 1999;Honda and Yasuda, 1999;Weber et al, 1999;Llanos et al, 2001;Zindy et al, 2003). This explains why inhibition of PP-1 activity could lead to observed p53 upregulation in rabbit and rat lens epithelial cells (Li et al, 1998(Li et al, , 2001a.…”

Section: Dephosphorylation Of P53 Displays Strong Impact On Its Functmentioning

confidence: 99%

Protein serine/threonine phosphatase-1 dephosphorylates p53 at Ser-15 and Ser-37 to modulate its transcriptional and apoptotic activities

et al. 2006

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We have previously demonstrated that the serine/threonine protein phosphatase-1 (PP-1) plays an important role in promoting cell survival. However, the molecular mechanisms by which PP-1 promotes survival remain largely unknown. In the present study, we provide evidence to show that PP-1 can directly dephosphorylate a master regulator of apoptosis, p53, to negatively modulate its transcriptional and apoptotic activities, and thus to promote cell survival. As a transcriptional factor, the function of p53 can be greatly regulated by phosphorylation and dephosphorylation. While the kinases responsible for phosphorylation of the 17 serine/threonine sites have been identified, the dephosphorylation of these sites remains largely unknown. In the present study, we demonstrate that PP-1 can dephosphorylate p53 at Ser-15 and Ser-37 through co-immunoprecipitation, in vitro and in vivo dephosphorylation assays, overexpression and silence of the gene encoding the catalytic subunit for PP-1. We further show that mutations mimicking constitutive dephosphorylation or phosphorylation of p53 at these sites attenuate or enhance its transcriptional activity, respectively. As a result of the changed p53 activity, expression of the downstream apoptosis-related genes such as bcl-2 and bax is accordingly altered and the apoptotic events are either largely abrogated or enhanced. Thus, our results demonstrate that PP-1 directly dephosphorylates p53, and dephosphorylation of p53 has as important impact on its functions as phosphorylation does. In addition, our results reveal that one of the molecular mechanisms by which PP-1 promotes cell survival is to dephosphorylate p53, and thus negatively regulate p53-dependent death pathway.

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Section: Dephosphorylation Of P53 Displays Strong Impact On Its Functmentioning

confidence: 99%

Protein serine/threonine phosphatase-1 dephosphorylates p53 at Ser-15 and Ser-37 to modulate its transcriptional and apoptotic activities

et al. 2006

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“…First, while the low levels of Mdm2 that are commonly observed in normal cells preferentially catalyse monoubiquitination of p53 (Li et al, 2003), ARF can not inhibit Mdm2-mediated monoubiquitination of p53 in vivo, although it can block p53 polyubiquitination (Xirodimas et al, 2001). Second, recent studies of p19 ARF demonstrated that ARF is able to cause cell cycle arrest independent of Mdm2 relocalisation to nucleoli and p53 stabilisation (Llanos et al, 2001;Korgaonkar et al, 2002). Thus, a critical question raised is how ARF can efficiently stabilise p53 in normal cells with low levels of Mdm2, a situation where Mdm2 is not solely responsible for p53 degradation.…”

Section: Arf-bp1 a Hect E3 Ubiquitin Ligase Plays An Important Rolementioning

confidence: 99%

ARF-BP1 as a potential therapeutic target

Chen

Brooks

2006

Br J Cancer

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In this review, we discuss the recent identification of ARF-BP1 (also known as Mule, UREB1, E3 histone , LASU1, and HectH9). ARF-BP1, a HECT domain-containing E3 ubiquitin ligase, interacts with ARF and p53. Its ubiquitin ligase activity is inhibited by ARF. Inactivation of ARF-BP1 stabilised p53 and induced apoptosis. Notably, inactivation of ARF-BP1 also caused cell growth repression in p53-null cells and breast cancer cells with mutant p53. Thus, ARF-BP1 emerges as a novel therapeutic target against cancer regardless of p53 status.

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“…This has led to conflicting views about how proteins in different sub-nuclear compartments can interact, most of which suggest movement of MDM2 into the nucleolus (Tao and Levine, 1999;Weber et al, 1999Weber et al, , 2000Zhang and Xiong, 1999;Lohrum et al, 2000). We have argued against this idea by showing that versions of human ARF that are excluded from the nucleolus remain capable of binding to MDM2 and stabilizing p53 (Llanos et al, 2001). One such variant, a fusion protein containing the N-terminal 29 residues of human ARF linked to GFP (GFP/2-29), is inherently unstable, but can be stabilized if redirected to the nucleolus by addition of an unrelated basic motif (Llanos et al, 2001;Rodway et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

“…We have argued against this idea by showing that versions of human ARF that are excluded from the nucleolus remain capable of binding to MDM2 and stabilizing p53 (Llanos et al, 2001). One such variant, a fusion protein containing the N-terminal 29 residues of human ARF linked to GFP (GFP/2-29), is inherently unstable, but can be stabilized if redirected to the nucleolus by addition of an unrelated basic motif (Llanos et al, 2001;Rodway et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

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Binding to nucleophosmin determines the localization of human and chicken ARF but not its impact on p53

et al. 2007

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The ARF tumour suppressor gene encodes a small highly basic protein whose known functions are largely determined by the amino acids encoded within the first exon. In mammals, the protein incorporates additional residues specified by an alternative reading frame in the second exon of INK4a, but this arrangement does not apply to the chicken homologue. In exploring the intracellular localization of chicken p7 ARF , we found that while the FLAG-and HA-tagged versions localize in the nucleolus, in line with mammalian ARF, the GFP-tagged version is excluded from the nucleolus. Here we show that irrespective of the source or composition of the ARF fusion proteins, versions that accumulate in the nucleolus share the ability to bind to nucleophosmin (NPM). Depletion of NPM with siRNA results in the re-location and destabilization of nucleolar forms of ARF but has little effect on the location or stability of a nucleoplasmic form of ARF. Importantly, knockdown of endogenous NPM does not impair the ability of ARF to bind to MDM2 and stabilize p53. These findings support the view that nucleolar localization determines the stability of ARF but not its primary function.

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Stabilization of p53 by p14ARF without relocation of MDM2 to the nucleolus

Cited by 247 publications

References 36 publications

Protein serine/threonine phosphatase-1 dephosphorylates p53 at Ser-15 and Ser-37 to modulate its transcriptional and apoptotic activities

Protein serine/threonine phosphatase-1 dephosphorylates p53 at Ser-15 and Ser-37 to modulate its transcriptional and apoptotic activities

ARF-BP1 as a potential therapeutic target

Binding to nucleophosmin determines the localization of human and chicken ARF but not its impact on p53

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