Authors: Chieh-Lin Teng, Yun-Chi Hsieh, Liem Phan, Jihyun Shin, Chris Gully, Guermarie Velazquez-Torres, Stephen Skerl, Sai-Ching J. Yeung, Shih-Lan Hsu and Mong-Hong Lee

Chieh-Lin Teng

Department of Molecular and Cellular Oncology; The University of Texas MD Anderson Cancer Center; Houston, TX USA; Division of Hematology/Medical Oncology; Department of Medicine; Taichung Veterans General Hospital; Taiwan; Department of Life Science; Tunghai University; Taiwan; Department of Medicine; Chung Shan Medical University; Taiwan

Yun-Chi Hsieh

Department of Molecular and Cellular Oncology; The University of Texas MD Anderson Cancer Center; Houston, TX USA; Department of Education & Research; Taichung Veterans General Hospital; Taichung, Taiwan

Liem Phan

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

Jihyun Shin

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

Chris Gully

Department of Molecular and Cellular Oncology; The University of Texas MD Anderson Cancer Center; Houston, TX USA; Program in Genes and Development; The University of Texas Graduate School of Biomedical Sciences at Houston; Houston, TX USA

Guermarie Velazquez-Torres

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

Stephen Skerl

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

Sai-Ching J. Yeung

Department of Emergency Medicine; The University of Texas MD Anderson Cancer Center; Houston, TX USA; Department of Endocrine Neoplasia and Hormonal Disorders; The University of Texas MD Anderson Cancer Center; Houston, TX USA

Shih-Lan Hsu

Department of Education & Research; Taichung Veterans General Hospital; Taichung, Taiwan

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; Program in Genes and Development; The University of Texas Graduate School of Biomedical Sciences at Houston; Houston, TX USA

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.

Received: August 26, 2012; Accepted: September 27, 2012; Published Online: October 24, 2012

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