SAPK pathways and p53 cooperatively regulate PLK4 activity and centrosome integrity under stress

Nakamura, Takanori; Saito, Haruo; Takekawa, Mutsuhiro

doi:10.1038/ncomms2752

Cited by 64 publications

(58 citation statements)

References 60 publications

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“…These data suggest that the presence of ARF suppresses Rasinduced centrosome amplification. Although p53 has been shown to prevent centrosome amplification (28)(29)(30), these data suggest a p53-independent function of ARF to protect cells from oncogenic Ras-mediated centrosome amplification. Taken together, our data suggest that ARF inhibits centrosome amplification.…”

Section: Trim28 Is a Novel Binding Partner Of Arfmentioning

confidence: 61%

“…p53 can prevent centrosome amplification in a transcriptionally dependent (29) or independent manner (30), although the underlying mechanisms remain poorly understood. Since it has been shown that p53 inactivation alone is insufficient to induce aneuploidy in the case of human diploid cells (45), it is likely that p53-independent factors are also involved in guarding the centrosome duplication process and maintaining chromosome stability.…”

Section: Discussionmentioning

confidence: 99%

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TRIM28 Is an E3 Ligase for ARF-Mediated NPM1/B23 SUMOylation That Represses Centrosome Amplification

Neo

Itahana

Alagu

et al. 2015

Molecular and Cellular Biology

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The tumor suppressor ARF enhances the SUMOylation of target proteins; however, the physiological function of ARF-mediated SUMOylation has been unclear due to the lack of a known, associated E3 SUMO ligase. Here we uncover TRIM28/KAP1 as a novel ARF-binding protein and SUMO E3 ligase for NPM1/B23. ARF and TRIM28 cooperate to SUMOylate NPM1, a nucleolar protein that regulates centrosome duplication and genomic stability. ARF-mediated SUMOylation of NPM1 was attenuated by TRIM28 depletion and enhanced by TRIM28 overexpression. Coexpression of ARF and TRIM28 promoted NPM1 centrosomal localization by enhancing its SUMOylation and suppressed centrosome amplification; these functions required the E3 ligase activity of TRIM28. Conversely, depletion of ARF or TRIM28 increased centrosome amplification. ARF also counteracted oncogenic Ras-induced centrosome amplification. Centrosome amplification is often induced by oncogenic insults, leading to genomic instability. However, the mechanisms employed by tumor suppressors to protect the genome are poorly understood. Our findings suggest a novel role for ARF in maintaining genome integrity by facilitating TRIM28-mediated SUMOylation of NPM1, thus preventing centrosome amplification. T he INK4a/ARF locus encodes two tumor suppressors, (i) p16INK4a , an inhibitor of cyclin-dependent kinase 4/6 (CDK4/ 6), and (ii) an alternative reading frame (ARF) protein (p14 ARF in humans and p19 ARF in mouse), referred to here as "ARF." This locus is mutated in approximately 40% of human cancers. ARF contributes to p53 stabilization and activation through inhibition of murine double minute 2 (MDM2), leading to cell cycle arrest, apoptosis, or senescence. Oncogenic insults such as mutations in Ras upregulate the expression of ARF to protect cells from tumorigenesis (1).There is substantial evidence that ARF has additional, p53-independent functions (2). For example, a broader spectrum of tumors was observed in ARF/p53-null mice than in p53-null mice (3). ARF is enriched within the nucleolus but also localizes to the mitochondria to induce apoptosis or autophagy in a p53-independent manner (2). These data support a role of ARF in p53-independent tumor-suppressive functions. However, the underlying mechanisms remain elusive.Interestingly, ARF has been shown to promote SUMOylation of MDM2 (4), nucleophosmin (NPM1/B23) (5), and the Werner helicase (WRN) (6) independently of p53. However, ARF did not stimulate SUMOylation in an in vitro reconstitution reaction in the presence of SUMO E1/E2 enzymes (6), suggesting that ARF is not the E3 SUMO ligase. The mechanism and biological impact of ARF-mediated SUMOylation are currently unclear.NPM1 has been shown to be involved in the p53-independent ARF pathway (7). NPM1 usually resides in the nucleolus but also shuttles between the nucleus and cytoplasm (8). SUMOylation of NPM1 contributes to its centrosomal localization (9), and NPM1 has been reported to exert tumor-suppressive function. For example, loss of NPM1 leads to centrosome amplification, resultin...

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Section: Trim28 Is a Novel Binding Partner Of Arfmentioning

confidence: 61%

Section: Discussionmentioning

confidence: 99%

TRIM28 Is an E3 Ligase for ARF-Mediated NPM1/B23 SUMOylation That Represses Centrosome Amplification

Neo

Itahana

Alagu

et al. 2015

Molecular and Cellular Biology

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“…Due to space limits, a few representative RNA transcripts are presented in Fig 1B as examples from the microarray to indicate the anticipated responses of these cells to p53 activation, including mRNAs, miRNAs and snoRNAs. According to previous studies, FAS, PUMA (BBC3), CDKN1A, MDM2, RRM2B (p53R2), BAX, CCNG1, TLR3 and MIR34A (miR-34a host gene) are upregulated upon p53 activation [27]; ACTB (β-actin), GAPDH, PSMB4 and C1orf43 are usually stably expressed [28]; whereas E2F1 [27], CCNE2 [29], POLD1 [30], CDCA8 [31], FBXO5 [32], PLK4 [33], BRCA1 [34], CCNB1 [35] and MIRH1 (miR-17-92 host gene) [36] are directly or indirectly repressed upon p53 activation (Fig 1B). Clustering analysis was employed to indicate the relative closeness of the reactive patterns how these genes respond to p53 activation in both cell lines.…”

Section: Resultsmentioning

confidence: 99%

p53 Represses the Oncogenic Sno-MiR-28 Derived from a SnoRNA

et al. 2015

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p53 is a master tumour repressor that participates in vast regulatory networks, including feedback loops involving microRNAs (miRNAs) that regulate p53 and that themselves are direct p53 transcriptional targets. We show here that a group of polycistronic miRNA-like non-coding RNAs derived from small nucleolar RNAs (sno-miRNAs) are transcriptionally repressed by p53 through their host gene, SNHG1. The most abundant of these, sno-miR-28, directly targets the p53-stabilizing gene, TAF9B. Collectively, p53, SNHG1, sno-miR-28 and TAF9B form a regulatory loop which affects p53 stability and downstream p53-regulated pathways. In addition, SNHG1, SNORD28 and sno-miR-28 are all significantly upregulated in breast tumours and the overexpression of sno-miR-28 promotes breast epithelial cell proliferation. This research has broadened our knowledge of the crosstalk between small non-coding RNA pathways and roles of sno-miRNAs in p53 regulation.

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“…In the absence of p53, function cells carrying amplified centrosomes are able to proliferate (Holland et al 2012). The complexity of this regulative network is heightened by the recent report that Plk4 is directly phosphorylated and activated by stress-activated protein kinase kinase kinases (SAPKKKs) to promote centrosome duplication (Nakamura et al 2013). However, this is balanced early in the stress response by stressinduced SAPK activation that prevents centrosome duplication.…”

Section: Tying Centriole Duplication To S Phasementioning

confidence: 99%