Authors: Chun-Chi Wu, Tsung-Ying Yang, Chang-Tze Ricky Yu, Liem Phan, Cristina Ivan, Anil K. Sood, Shih-Lan Hsu and Mong-Hong Lee

Chun-Chi Wu

Institute of Medicine; Chung Shan Medical University; Taichung, Taiwan, Republic of China and Department of Medical Research, Chung-Shan Medical University Hospital Taichung, Taiwan, Republic of China

Tsung-Ying Yang

Division of Chest Medicine; Department of Internal Medicine; Taichung Veterans General Hospital; Taichung, Taiwan, Republic of China; Department of Molecular and Cellular Oncology; The University of Texas MD Anderson Cancer Center; Houston, TX USA

Chang-Tze Ricky Yu

Department of Applied Chemistry; National Chi Nan University; Nantou, Taiwan, Republic of China

Liem Phan

Department of Molecular and Cellular Oncology; The University of Texas MD Anderson Cancer Center; Houston, TX USA

Cristina Ivan

Departments of Gyn Onc and Reproductive Medicine and Cancer Biology; The University of Texas MD Anderson Cancer Center; Houston, TX USA

Anil K. Sood

Departments of Gyn Onc and Reproductive Medicine and Cancer Biology; The University of Texas MD Anderson Cancer Center; Houston, TX USA

Shih-Lan Hsu

Corresponding author: h2326@vghtc.gov.tw
Institute of Medicine; Chung Shan Medical University; Taichung, Taiwan, Republic of China and Department of Medical Research, Chung-Shan Medical University Hospital Taichung, Taiwan, Republic of China; Division of Chest Medicine; Department of Internal Medicine; Taichung Veterans General Hospital; Taichung, Taiwan, Republic of China; Department of Education & Research; Taichung Veterans General Hospital; Taichung, Taiwan, Republic of China

Mong-Hong Lee

Corresponding author: mhlee@mdanderson.org
Department of Molecular and Cellular Oncology; The University of Texas MD Anderson Cancer Center; Houston, TX USA; Program in Cancer Biology; The University of Texas Graduate School of Biomedical Sciences at Houston; Houston, TX USA

Abstract:
p53 plays an important role in mitotic checkpoint, but what its role is remains enigmatic. Aurora A is a Ser/Thr kinase involved in correcting progression of mitosis. Here, we show that p53 is a negative regulator for Aurora A. We found that p53 deficiency leads to Aurora A elevation. Ectopic expression of p53 or DNA damage-induced expression of p53 can suppress the expression of Aurora A. Mechanistic studies show that p53 is a negative regulator for Aurora A expression through both transcriptional and posttranslational regulation. p53 knockdown in cancer cells reduces the level of p21, which, in turn, increases the activity of CDK2 followed by induction of Rb1 hyperphosphorylation and its dissociation with transcriptional factor E2F3. E2F3 can bind to Aurora A gene promoter, potentiating Aurora A gene expression and p53 deficiency, enhancing the binding of E2F3 on Aurora A promoter. Also, p53 deficiency leads to decelerating Aurora A’s turnover rate, due to the fact that p53 deficiency causes the downregulation of Fbw7α, a component of E3 ligase of Aurora A. Consistently, p53 knockdown-mediated Aurora A elevation is mitigated when Fbw7α is ectopically expressed. Thus, p53-mediated Aurora A degradation requires Fbw7α expression. Significantly, inverse correlation between p53 and Aurora A elevation is translated into the deregulation of centrosome amplification. p53 knockdown leads to high percentages of cells with abnormal amplification of centrosome. These data suggest that p53 is an important negative regulator of Aurora A, and that loss of p53 in many types of cancer could lead to abnormal elevation of Aurora A and dysregulated mitosis, which provides a growth advantage for cancer cells.

Received: June 27, 2012; Accepted: August 3, 2012; Published Online: August 16, 2012

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