Roles of cyclins A and E in induction of centrosome amplification in p53-compromised cells

Hanashiro, Kazuhiko; Kanai, Masayuki; Geng, Yan; Siciński, Piotr; Fukasawa, Kenji

doi:10.1038/onc.2008.161

Cited by 45 publications

(39 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As expected, introduction of the CAT mutant alone resulted in an increase in the frequency of centrosome amplification (column 2, 480%) compared with the control cells (column 1, B60%). As described previously (Hanashiro et al, 2008), cyclin E À/À cells silenced for cyclin A expression failed to re-duplicate centrosomes (column 3, B30% of centrosome amplification frequency, which is equivalent to that occurring during the pre-arresting period). However, co-expression of the CAT mutant restored the ability to undergo centrosome re-duplication (column 4), showing that overexpression of the active ROCK II can by-pass the requirement of the CDK2 activity for centrosome duplication/centrosome amplification.…”

Section: Resultssupporting

confidence: 56%

“…Thus, depletion of both cyclin E and cyclin A abolishes the intracellular CDK2 activity, leading to inability to initiate centrosome duplication (Hanashiro et al, 2008). We used this finding as an experimental system to further test ROCK II as a key and sufficient downstream effector of CDK2 to initiate centrosome duplication.…”

Section: Resultsmentioning

confidence: 99%

“…We used this finding as an experimental system to further test ROCK II as a key and sufficient downstream effector of CDK2 to initiate centrosome duplication. MEFs derived from mice deficient for both cyclin E1 and cyclin E2 isoforms, which were stably transfected with DN p53 (Geng et al, 2003;Hanashiro et al, 2008), were pre-arrested with Aph, and cotransfected with either GFP-vector or GFP-CAT and either small interfering RNA (siRNA) sequence specific for cyclin A or the control siRNA sequence. Cells were further incubated in the presence of Aph for 48 h. After confirming the successful silencing of cyclin A expression and expression of the CAT mutant Figure 1 Expression of constitutively active ROCK II by-passes the requirement of CDK2 for the initiation of centrosome duplication during the cell cycle.…”

Section: Resultsmentioning

confidence: 99%

See 2 more Smart Citations

Activated ROCK II by-passes the requirement of the CDK2 activity for centrosome duplication and amplification

2011

Self Cite

View full text Add to dashboard Cite

Initiation of centrosome duplication and DNA replication is coupled, which is primarily achieved by the late G1 phase-specific activation of cyclin-dependent kinase 2 (CDK2)-cyclin E, which triggers both centrosome duplication and DNA replication. Uncoupling of these two events contributes to overduplication of centrosomes, resulting in the presence of more than two centrosomes (centrosome amplification). Centrosome amplification, which is frequently observed in cancers, contributes to tumor development through destabilizing genomes. Nucleophosmin (NPM/B23) is one of the phosphorylation targets of CDK2-cyclin E for the initiation of centrosome duplication. It has been found that NPM/B23 phosphorylated on Thr199 by CDK2-cyclin E acquires a high binding affinity to ROCK II kinase. The Thr199-phosphorylated NPM/B23 physically interacts with and super-activates the centrosomally localized ROCK II, which is a critical event for centrosomes to initiate duplication. Here, we provide direct evidence for the activation of ROCK II as a primary and sufficient downstream event of CDK2-cyclin E for the initiation of centrosome duplication and for the induction of centrosome amplification.

show abstract

Section: Resultssupporting

confidence: 56%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Activated ROCK II by-passes the requirement of the CDK2 activity for centrosome duplication and amplification

2011

Self Cite

View full text Add to dashboard Cite

show abstract

“…Analysis of cyclin E-deficient fibroblasts has indicated that the requirement for either cyclin in allowing centrosome duplication changes during the cell cycle, with cyclin E being primarily involved in licensing the centrosome for duplication during G1 early S-phase (Wong and Stearns, 2003) and cyclin A being more involved in damage-induced amplification, which is believed to occur during G2 phase (Dodson et al, 2004;Hanashiro et al, 2008). Moreover, cyclin E overexpression in p53-deficient mouse cells induced centrosome amplification, but little impact was seen in wild-type rat or mouse fibroblasts (Spruck et al, 1999;Mussman et al, 2000).…”

Section: Resultsmentioning

confidence: 99%

DNA damage induces Chk1-dependent threonine-160 phosphorylation and activation of Cdk2

et al. 2009

View full text Add to dashboard Cite

“…P53 operates as a tumor suppressor mainly as a transcription factor that directly binds to the promoter region of target genes and activates or suppresses their transcription (14). Importantly, centrosome homeostasis is disrupted in cancer cells lacking p53 function due to deregulated activity of cdk2 kinase and consequent abrogation of cell cycle checkpoints resulting in centrosome amplification and CIN (7,15,16). In breast cancer, absence of p53 function has been associated with an aggressive phenotype characterized by CIN, hormone independence, resistance to anticancer drugs and poor prognosis (17).…”

Section: Introductionmentioning

confidence: 99%

Abrogation of p53 function leads to metastatic transcriptome networks that typify tumor progression in human breast cancer xenografts

et al. 2010

View full text Add to dashboard Cite

Abstract. Development of chromosomal instability (CIN) and consequent phenotypic heterogeneity represent common events during breast cancer progression. Breast carcinomas harboring extensive chromosomal aberrations display a more aggressive behavior characterized by chemoresistance and the propensity to give rise to distant metastases. The tumor suppressor p53 plays a key role in the maintenance of chromosomal stability and tissue homeostasis through activation of cell cycle checkpoints following DNA damage and control of centrosome duplication that ensures equal chromosome segregation during cell division. Furthermore, p53 suppresses CD44 expression and the acquisition of stem cell-like properties responsible for epithelial to mesenchymal transition (EMT) and metastasis. In this study we employed MCF-7 breast cancer cells with endogenous wild-type p53, an engineered ) overexpressing a dominant negative p53val135 mutant, and cells re-cultured from vMCF-7 DNP53 tumor xenografts. We carried out an integrative transcriptome and cytogenetic analysis to characterize the mechanistic linkage between loss of p53 function, EMT and consequent establishment of invasive gene signatures during breast cancer progression. We demonstrate that abrogation of p53 function drives the early transcriptome changes responsible for cell proliferation, EMT and survival, while further transcriptome changes that occur during in vivo tumor progression are mechanistically linked to the development of CIN leading to a more invasive and metastatic breast cancer phenotype. Here we identified distinct novel non-canonical transcriptome networks involved in cell proliferation, EMT, chemoresistance and invasion that arise following abrogation of p53 function in vitro and development of CIN in vivo. These studies also have important translational implications since some of the nodal genes identified here are 'druggable' making them appropriate molecular targets for the treatment of breast carcinomas displaying mutant p53, EMT, CIN and high metastatic potential. IntroductionHuman breast tumors displaying an aggressive behavior are generally characterized by high tumor cell heterogeneity, which has been associated with the development of chromosomal instability (CIN) during tumor progression (1,2). Chromosomal instability represents a hallmark of solid tumors and is characterized by the high frequency of qualitative and quantitative chromosome abnormalities that arise during tumor progression (3). Centrosome duplication plays a critical role in the control of chromosomal stability through the establishment of bipolar mitotic spindles and propagation of a diploid karyotype (4,5). In normal cells, centrosome duplication is coordinated with DNA replication, ensuring the establishment of bipolar mitotic spindle leading to equal chromosome segregation (6-8). Although chromosomal instability may be present during the early stages of neoplastic transformation, the persistence of CIN during tumor progression and its causative role in the development of dista...

show abstract

Roles of cyclins A and E in induction of centrosome amplification in p53-compromised cells

Cited by 45 publications

References 28 publications

Activated ROCK II by-passes the requirement of the CDK2 activity for centrosome duplication and amplification

Activated ROCK II by-passes the requirement of the CDK2 activity for centrosome duplication and amplification

DNA damage induces Chk1-dependent threonine-160 phosphorylation and activation of Cdk2

Abrogation of p53 function leads to metastatic transcriptome networks that typify tumor progression in human breast cancer xenografts

Contact Info

Product

Resources

About