p53 Localizes to the Centrosomes and Spindles of Mitotic Cells in the Embryonic Chick Epiblast, Human Cell Lines, and a Human Primary Culture: An Immunofluorescence Study

Morris, Valerie B.; Brammall, Jennifer; Noble, Jane R.; Reddel, Roger R.

doi:10.1006/excr.2000.4800

Cited by 76 publications

(53 citation statements)

References 37 publications

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“…As shown in Figure 3, while prophase chromosomes were condensed, hTERT and p53 became dissociated from chromosomes. In metaphase, the majority of hTERT and p53 became distributed to the positions potentially interacting with microtubule spindles, consistent with previous ®ndings that p53 binds to microtubule spindles in three di erent human cell lines (Morris et al, 2000). In anaphase, the twodaughter chromatids were separated and hTERT and p53 were seen to surround the chromatids with substantial amounts of hTERT and p53 at the equatorial plate.…”

Section: Resultssupporting

confidence: 89%

“…Consistent with previous ®ndings that p53 is also involved in mitotic spindle function in human cells (Morris et al, 2000) and co-immunoprecipitates with telomerase from breast cancer cells (Li et al, 1999), the present study shows that p53 shares a similar subcellular distribution pattern with that of hTERT under immuno¯uorescent microscopy throughout mitosis. It may thus be possible that hTERT and p53 cooperate to maintain normal mitotic spindle function during chromosome segregation.…”

Section: Discussionsupporting

confidence: 92%

“…To compare the e ect on cell death of lowering hTERT with that mediated by alterations in the p53 pathway, p53 was over-and under-expressed in PMC42 cells. Transient transfection of p53 antisense RNA induced signi®cant cell death; transient overexpression of p53 wild type for 24 h resulted in higher cell survival levels than in vector transfected controls (Figure 1c), con®rming that p53 operates to protect the cells probably against genome instability (Morris et al, 2000).…”

Section: Resultsmentioning

confidence: 81%

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TERT regulates cell survival independent of telomerase enzymatic activity

Cao¹,

He²,

Deb³

et al. 2002

Oncogene

197

139

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Human telomerase reverse transcriptase (hTERT), the catalytic subunit of telomerase, plays a pivotal role in the maintenance of telomeres and cell proliferation. Here we report that down-regulation of hTERT induces apoptosis independently of telomerase enzymatic activity in human breast cancer cells. Expression of a hTERT mutant lacking telomerase activity rescues the cells with lowered telomerase without inducing cell death. With similar patterns of subcellular distribution to that of the tumor suppressor protein p53 during mitosis, hTERT interacts with p53 and poly(ADP-ribose) polymerase (PARP). Decreasing p53 expression in intact cells worsens, and increasing p53 prevents, cell death induced by lowering hTERT. Thus, hTERT maintains cell survival and proliferation via both telomerase enzymatic activitydependent telomere lengthening and enzymatic activityindependent intermolecular interactions involving p53 and PARP.

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Section: Resultssupporting

confidence: 89%

Section: Discussionsupporting

confidence: 92%

Section: Resultsmentioning

confidence: 81%

See 1 more Smart Citation

TERT regulates cell survival independent of telomerase enzymatic activity

Cao¹,

He²,

Deb³

et al. 2002

Oncogene

197

139

View full text Add to dashboard Cite

show abstract

“…Using this experimental system, we could identify the transactivation function-independent regulation of centrosome duplication by p53. A number of studies have shown centrosomal association of p53 (Blair Zajdel and Blair, 1988;Brown et al, 1994;Morris et al, 2000;Ciciarello et al, 2001;Tarapore et al, 2001b), although the role of centrosomally localized p53 in the regulation of centrosome duplication has been unclear. When we examined the potential effect of mortalin on centrosomal localization of p53, we found that mortalin promoted dissociation of p53 from centrosomes.…”

Section: Discussionmentioning

confidence: 99%

“…As a number of studies have shown that p53 is present at centrosomes (Blair Zajdel and Blair, 1988;Brown et al, 1994;Morris et al, 2000;Ciciarello et al, 2001;Tarapore et al, 2001b), we next examined whether mortalin affects the centrosomal localization of p53. The mortalin-binding region of mouse p53 has been previously identified to a.a. 312-352 (a.a. 314-355 of human p53) .…”

Section: Mortalin Drives Centrosome Duplication Through Blocking the mentioning

confidence: 99%

Mortalin controls centrosome duplication via modulating centrosomal localization of p53

Izumi

Kanai

et al. 2006

Oncogene

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Abnormal amplification of centrosomes, commonly found in human cancer, is the major cause of mitotic defects and chromosome instability in cancer cells. Like DNA, centrosomes duplicate once in each cell cycle, hence the defect in the mechanism that ensures centrosome duplication to occur once and only once in each cell cycle results in abnormal amplification of centrosomes and mitotic defects. Centrosomes are non-membranous organelles, and undergo dynamic changes in its constituents during the centrosome duplication cycle. Through a comparative mass spectrometric analysis of unduplicated and duplicated centrosomes, we identified mortalin, a member of heat shock protein family, as a protein that associates preferentially with duplicated centrosomes. Further analysis revealed that mortalin localized to centrosomes in late G1 before centrosome duplication, remained at centrosomes during S and G2, and dissociated from centrosomes during mitosis. Overexpression of mortalin overrides the p53-dependent suppression of centrosome duplication, and mortalin-driven centrosome duplication requires physical interaction between mortalin and p53. Moreover, mortalin promotes dissociation of p53 from centrosomes through physical interaction. The p53 mutant that lacks the ability to bind to mortalin remains at centrosomes, and suppresses centrosome duplication in a transactivation function-independent manner. Thus, our present findings not only identify mortalin as an upstream molecule of p53 but also provide evidence for the involvement of centrosomally localized p53 in the regulation of centrosome duplication.

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Aurora A kinase is required for activation of the Fanconi anemia/BRCA pathway upon DNA damage

et al. 2016

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Previous studies have linked the DNA damage response to mitotic progression machinery. Mitotic kinases, such as Aurora A kinase and Polo‐like kinase, are involved in the phosphorylation of cell cycle regulators in response to DNA damage. Here, we investigated the potential involvement of Aurora A kinase in the activation of the Fanconi anemia ( FA )/ BRCA pathway, which participates in cellular response to DNA interstrand cross‐link lesions ( ICL ). Initially, we detected interactions between Aurora A kinase and FANCA protein, one of the components of the FA nuclear core complex. Silencing of Aurora A kinase led to inhibition of monoubiquitination of FANCD 2 and formation of nuclear foci, the final consequences of FA / BRCA pathway activation upon ICL induction. An in vitro kinase assay revealed that Aurora A kinase phosphorylates S165 of FANCA . Moreover, this phosphorylation event was induced by the treatment with mitomycin C ( MMC ), an ICL ‐inducing agent. In cells overexpressing S165A mutant FANCA , monoubiquitination of FANCD 2 and nuclear foci formation was impaired and cellular sensitivity to MMC was enhanced. These results suggest that S165 phosphorylation by Aurora A kinase is required for proper activation of the FA / BRCA pathway in response to DNA damage.

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p53 Localizes to the Centrosomes and Spindles of Mitotic Cells in the Embryonic Chick Epiblast, Human Cell Lines, and a Human Primary Culture: An Immunofluorescence Study

Cited by 76 publications

References 37 publications

TERT regulates cell survival independent of telomerase enzymatic activity

TERT regulates cell survival independent of telomerase enzymatic activity

Mortalin controls centrosome duplication via modulating centrosomal localization of p53

Aurora A kinase is required for activation of the Fanconi anemia/BRCA pathway upon DNA damage

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