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: 5.01). 09/2012; 11(20):3719. DOI: 10.4161/cc.22113
Source: PubMed

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

  • 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.
    Cell cycle (Georgetown, Tex.) 10/2012; 11(21). DOI:10.4161/cc.22381 · 5.01 Impact Factor
  • 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.
    Cell cycle (Georgetown, Tex.) 02/2013; 12(7). DOI:10.4161/cc.24004 · 5.01 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Polo-like kinase 1 has been established as one of the most attractive targets for molecular cancer therapy. In fact, multiple small-molecule inhibitors targeting this kinase have been developed and intensively investigated. Recently, it has been reported that the cytotoxicity induced by Plk1 inhibition is elevated in cancer cells with inactive p53, leading to the hypothesis that inactive p53 is a predictive marker for the response of Plk1 inhibition. In our previous study based on different cancer cell lines, we showed that cancer cells with wild type p53 were more sensitive to Plk1 inhibition by inducing more apoptosis, compared with cancer cells depleted of p53. In the present work, we further demonstrate that in the presence of mitotic stress induced by different agents, Plk1 inhibitors strongly induced apoptosis in HCT116 p53 (+/+) cells, whereas HCT116 p53 (-/-) cells arrested in mitosis with less apoptosis. Depletion of p53 in HCT116 p53 (+/+) or U2OS cells reduced the induction of apoptosis. Moreover, the surviving HCT116 p53 (-/-) cells showed DNA damage and a strong capability of colony formation. Plk1 inhibition in combination with other anti-mitotic agents inhibited proliferation of tumor cells more strongly than Plk1 inhibition alone. Taken together, the data underscore that functional p53 strengthens the efficacy of Plk1 inhibition alone or in combination by strongly activating cell death signaling pathways. Further studies are required to investigate if the long-term outcomes of losing p53, such as low differential grade of tumor cells or defective DNA damage checkpoint, are responsible for the cytotoxicity of Plk1 inhibition.
    Cell cycle (Georgetown, Tex.) 04/2013; 12(9). DOI:10.4161/cc.24573 · 5.01 Impact Factor


Available from