p53-Aurora A mitotic feedback loop regulates cell cycle progression and genomic stability

Simmons Comprehensive Cancer Center and Department of Biochemistry and Department of Pharmacology
Cell cycle (Georgetown, Tex.) (Impact Factor: 4.57). 09/2012; 11(20):3719. DOI: 10.4161/cc.22113
Source: PubMed


Comment on: Wu C-C, et al. Cell Cycle 2012; 11:3433-42.

Download full-text


Available from: · License: CC BY-NC
  • Source
    • "p53 is localized at centrosomes, mitotic spindles, the centromeres, the midzone/cleavage furrow in mitosis [121-123] and is activated in response to various mitotic stresses such as aberrant spindle formation, abnormal centrosome separation and chromosome damage or missegregation [124-126], suggestive of p53 role in mitosis. p53 knockdown leads to high percentages of cells with abnormal amplification of centrosomes [10,127] and p53 is an important negative regulator of the mitotic kinase Aurora A [128]. p53 localization at the centrosomes in mitosis is ataxia-telangiectasia mutated (ATM)-dependent and monitors mitotic spindle integrity in mitosis [122,129,130], leading to the proposal that ATM and p53 might contribute to the “centrosomal checkpoint”, a network that integrates cell cycle arrest and repair signals [131,132]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Polo-like kinase 1, a pivotal regulator of mitosis and cytokinesis, is highly expressed in a broad spectrum of tumors and its expression correlates often with poor prognosis, suggesting its potential as a therapeutic target. p53, the guardian of the genome, is the most important tumor suppressor. In this review, we address the intertwined relationship of these two key molecules by fighting each other as eternal rivals in many signaling pathways. p53 represses the promoter of Polo-like kinase 1, whereas Polo-like kinase 1 inhibits p53 and its family members p63 and p73 in cancer cells lacking functional p53. Plk1 inhibitors target all rapidly dividing cells irrespective of tumor cells or non-transformed normal but proliferating cells. Upon treatment with Plk1 inhibitors, p53 in tumor cells is activated and induces strong apoptosis, whereas tumor cells with inactive p53 arrest in mitosis with DNA damage. Thus, inactive p53 is not associated with a susceptible cytotoxicity of Polo-like kinase 1 inhibition and could rather foster the induction of polyploidy/aneuploidy in surviving cells. In addition, compared to the mono-treatment, combination of Polo-like kinase 1 inhibition with anti-mitotic or DNA damaging agents boosts more severe mitotic defects, effectually triggers apoptosis and strongly inhibits proliferation of cancer cells with functional p53. In this regard, restoration of p53 in tumor cells with loss or mutation of p53 will reinforce the cytotoxicity of combined Polo-like kinase 1 therapy and provide a proficient strategy for combating relapse and metastasis of cancer.
    Full-text · Article · Jul 2013 · Oncotarget
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: FBXW7, a component of E3 ubiquitin ligase, plays an important role in mitotic checkpoint, but its role remains unclear. Aurora B is a mitotic checkpoint kinase that plays a pivotal role in mitosis by ensuring correct chromosome segregation and normal progression through mitosis. Whether Aurora B and FBXW7 are coordinately regulated during mitosis is not known. Here, we show that FBXW7 is a negative regulator for Aurora B. Ectopic expression of FBXW7 can suppress the expression of Aurora B. Accordingly, FBXW7 deficiency leads to Aurora B elevation. Mechanistic studies show that all FBXW7 isoforms are negative regulators of Aurora B expression through ubiquitination-mediated protein degradation. Aurora B interacts with R465 and R505 residues of WD 40 domain of FBXW7. Significantly, inverse correlation between FBXW7 and Aurora B elevation is translated into the deregulation of mitosis. FBWX7 expression mitigates Aurora B-mediated cell growth and mitotic deregulation. In addition, FBXW7 reduces the percentage of multinucleated cells caused by Aurora B overexpression. These data suggest that FBXW7 is an important negative regulator of Aurora B, and that the loss or mutation of FBXW7 as seen in many types of cancer could lead to an abnormal elevation of Aurora B and result in deregulated mitosis, which accelerates cancer cell growth.
    Full-text · Article · Oct 2012 · Cell cycle (Georgetown, Tex.)
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Aurora kinase B is a critical component of the chromosomal passenger complex, which is involved in the regulation of microtubule-kinetochore attachments and cytokinesis. By using conditional knockout cells and chemical inhibition, we show here that inactivation of Aurora B results in delayed G₁/S transition and premature mitotic exit. Aurora B deficiency results in delayed DNA replication in cultured fibroblasts as well as liver cells after hepatectomy. This is accompanied by increased transcription of the cell cycle inhibitor p21 (Cip1) . Lack of Aurora B does not prevent mitotic entry but results in a premature exit from prometaphase in the presence of increased p21 (Cip1) -Cdk1 inactive complexes. Aurora B-null cells display reduced degradation of cyclin B1, suggesting the presence of phenomenon known as adaptation to the mitotic checkpoint, previously described in yeast. Concomitant elimination of p21 (Cip1) rescues Cdk1 activity and prevents premature mitotic exit in Aurora B-deficient cells. These results suggest that Aurora B represses p21 (Cip1) , preventing delayed DNA replication, Cdk inhibition and premature mitotic exit. The upregulation of p21 (Cip1) observed after inhibition of Aurora B may have important implications in cell cycle progression, tetraploidy, senescence or cancer therapy.
    Full-text · Article · Feb 2013 · Cell cycle (Georgetown, Tex.)
Show more