Direct evidence for the role of centrosomally localized p53 in the regulation of centrosome duplication

Shinmura, Kazuya; Bennett, Richard A. O.; Tarapore, Pheruza; Fukasawa, Kenji

doi:10.1038/sj.onc.1210085

Cited by 89 publications

(76 citation statements)

References 34 publications

(40 reference statements)

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“…These abnormalities resulted into apoptosis of cells both in interphase and pro-metaphase stages. Wild type p53 plays an essential role in control of centrosome duplication; its loss or mutational inactivation has been associated with a high rate of aneuploidy in cancers (25,(33)(34)(35). In light of these reports and our data on activation of p53 with CARF up-regulation (Figs.…”

Section: Waf1supporting

confidence: 52%

CARF Is a Vital Dual Regulator of Cellular Senescence and Apoptosis

Hasan

Cheung

Kaul

et al. 2009

Journal of Biological Chemistry

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The tumor suppressor protein, p53, is central to the pathways that monitor the stress, DNA damage repair, cell cycle, aging, and cancer. Highly complex p53 networks involving its upstream sensors and regulators, downstream effectors and regulatory feedback loops have been identified. CARF (Collaborator of ARF) was shown to enhance ARF-dependent and -independent wild-type p53 function. Here we report that (i) CARF overexpression causes premature senescence of human fibroblasts, (ii) it is vital for replicative and stress-induced senescence, and (iii) the lack of CARF function causes aneuploidy and apoptosis. We provide evidence that CARF plays a dual role in regulating p53-mediated senescence and apoptosis, the two major tumor suppressor mechanisms.The tumor suppressor protein, p53, is the most frequently inactivated protein in human cancers that symbolizes deregulation of genomic stability, cell cycle, senescence, and stress damage-repair response of cells (1-5). p53 signaling has been established as a complex network comprised of (i) upstream components consisting of stress signals and sensor proteins including kinases, transferases, methyalses, ligases, and others that regulate its activity either by post-translational modifications or by subcellular localization, (ii) core regulators including an upstream positive regulator (alternative reading frame, ARF) 4 protein that blocks its downstream effector and antagonist human double minute-2 (HDM2) protein, and (iii) the downstream effectors that determine the fate of cells by instigation of growth arrest, senescence, or apoptosis, the three potent tumor suppressor mechanisms. In addition to the fact that the initiation of DNA damage-induced senescence and establishment of growth arrest require p53 activation (4), a large number of studies have shown that the persistent inactivation of p53 is required for tumor maintenance. Cancer cells undergo either growth arrest or apoptosis with restoration of wild-type p53 function in vitro and in vivo (6 -8). These studies have prioritized further understanding of p53 signaling and regulation that would have major impact in cancer drug development.It is yet to be resolved how functional restoration of p53 culminates to growth arrest/senescence in some cells and apoptosis in others. Is it driven by the level of p53 expression, modulating partner proteins or its upstream regulators? Among the large number of p53-binding proteins that influence its activities, ARF and HDM2 have been demonstrated as its major regulators. HDM2 (an E3 ubiquitin ligase) is transcriptionally activated by p53 and acts to degrade p53 in turn; thus, executing a negative feedback loop on p53 activity. ARF has been shown to bind and inhibit HDM2 activity resulting in the activation of p53 pathway (9). CARF (Collaborator of ARF) protein was initially cloned as an ARF-binding protein by yeast two-hybrid screening and was shown to activate ARF-dependent and -independent p53 functions (10 -13). CARF interacts not only with ARF but also with p53 and HDM2, an...

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Section: Waf1supporting

confidence: 52%

CARF Is a Vital Dual Regulator of Cellular Senescence and Apoptosis

Hasan

Cheung

Kaul

et al. 2009

Journal of Biological Chemistry

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“…It remains to be determined whether the interaction between BRCA2 and BCCIP plays a direct role in cytokinesis. In addition, it has been reported that p53 protein has both transcription-dependent and -independent role in preventing centrosome amplification (Tarapore et al, 2001;Tarapore and Fukasawa, 2002;Shinmura et al, 2006), and the transcriptional-dependent function of p53 in centrosome amplification is likely mediated by p21 (Tarapore et al, 2001) and BCCIP interacts with p21 (Meng et al, 2004a, b) and BCCIP down-regulation abrogates the transcriptional activity of p53 (Meng et al, 2007). It is possible that BCCIP may regulate centrosome stability through p53 and p21 functions.…”

Section: Discussionmentioning

confidence: 99%

Roles of BCCIP in chromosome stability and cytokinesis

Meng

Fan²,

Shen

2007

Oncogene

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The BRCA2 gene is involved in recombinational DNA repair and cytokinesis. BRCA2 defects are associated with chromosomal abnormalities, which is a hallmark of genomic instability that contributes to tumorigenesis. Here, we show that downregulation of a BRCA2 interacting protein (BCCIP) in HT1080 cells leads to chromosomal polyploidization, centrosome amplification and abnormal mitotic spindle formation. The BCCIP knockdown cells can enter mitosis and retain spindle checkpoint, but fail to complete cytokinesis. Our data suggest an essential role of BCCIP in the maintenance of genomic integrity.

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“…Tumour suppressor proteins including BRCA1 and p53 have also been found to co-localize with centrosomes in mitosis, although how these proteins participate in centrosome regulation it is not known. It is also unknown if they impact on centrosome stability in the context of mitotic DNA damage (Hsu and White, 1998;Kais and Parvin, 2008;Shinmura et al, 2007;Fukasawa, 2007).…”

Section: Growing Evidence Of Centrosomal Checkpoints Responding To Dnmentioning

confidence: 99%

An ATM- and ATR-dependent checkpoint inactivates spindle assembly by targeting CEP63

Smith¹,

Dejsuphong

Balestrini³

et al. 2009

Nat Cell Biol

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The effects of ATM and ATR signalling induced by chromosomal breakage have been described extensively in modulating cell cycle progression up to the onset of mitosis.However, DNA damage checkpoint responses in mitotic cells are not well understood.This thesis reports on the effects of double strand breaks on the progression of mitosis.We found ATM and ATR activation can occur in mitotic Xenopus laevis egg extract and the induction of ATM and ATR by chromosomal breakages inhibits spindle assembly in both Xenopus egg extract and somatic cells. The delay in mitotic progression induced by ATM and ATR was found not to involve major spindle assembly factors activities such as, Cdk1, Plx1 and RCC1/Ran-GTP. However, normal anastral spindles formation around linear DNA coated beads, which can activate ATM and ATR, linked centrosome-driven spindle assembly to ATM and ATR dependent spindle defects. cDNA expression library screening was undertaken to identify novel ATM and ATR targets in this mitotic checkpoint pathway, through which the novel centrosomal protein XCEP63 was identified as a likely candidate. Data obtained from depletion and reconstitution of XCEP63 in Xenopus egg extract established that normal centrosome-driven spindle assembly requires XCEP63. Moreover, ATM and ATR phosphorylates XCEP63 on serine 560 and promotes delocalisation from the centrosome. ATM and ATR inhibition or addition of non-phosphorylable XCEP63 recombinant protein mutated at serine 560 prevents spindle assembly abnormalities.These findings suggest that ATM and ATR regulate mitotic events by targeting XCEP63 and centrosome-dependent spindle assembly. This pathway may provide support for DNA repair processes or regulate cell survival in the presence of mitotic DNA damage. 3

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Direct evidence for the role of centrosomally localized p53 in the regulation of centrosome duplication

Cited by 89 publications

References 34 publications

CARF Is a Vital Dual Regulator of Cellular Senescence and Apoptosis

CARF Is a Vital Dual Regulator of Cellular Senescence and Apoptosis

Roles of BCCIP in chromosome stability and cytokinesis

An ATM- and ATR-dependent checkpoint inactivates spindle assembly by targeting CEP63

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