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Carcinogenesis Advance Access originally published online on August 8, 2007
Carcinogenesis 2007 28(12):2467-2475; doi:10.1093/carcin/bgm185
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Role of p14ARF in TWIST-mediated senescence in prostate epithelial cells

Wai Kei Kwok, Ming-Tat Ling, Hiu Fung Yuen1, Yong-Chuan Wong and Xianghong Wang*

Department of Anatomy
1 Department of Pathology, Faculty of Medicine, The University of Hong Kong, 21 Sassoon Road, Hong Kong SAR, China

* To whom correspondence should be addressed. Tel: +852 2819 2867; Fax: +852 2817 0857; Email: xhwang{at}hkucc.hku.hk

Correspondence may also be addressed to Y-C.Wong. Tel: +852 2819 9226; Fax: +852 2817 0857; Email: ycwong{at}hkucc.hku.hk

Recently, TWIST, a basic helix–loop–helix transcription factor, is suggested to be an oncogene because of its over-expression in many types of human cancer and its positive role in promoting cell survival. The aim of this study was to investigate the role of TWIST on the growth of human epithelial cells. Using two immortalized human prostate epithelial cell lines, we demonstrated that inactivation of TWIST by small RNA technology led to the promotion of cellular senescence and growth arrest, suggesting that TWIST plays a key role in the continuous proliferation of immortalized cells. Over-expression of TWIST, in contrast, resulted in suppression of cellular senescence in response to genotoxic damage and promotion of cell proliferation with DNA damage accumulation, indicating that TWIST promotes genomic instability. In addition, we also found that the TWIST-mediated cellular senescence was regulated through its negative effect on p14ARF and subsequent suppression of MDM2/p53 and Chk1/2 DNA damage response pathways. Our results suggest that over-expression of TWIST results in down-regulation of p14ARF, which leads to the impairment of DNA damage checkpoint in response to genotoxic stress. This negative effect of TWIST on DNA damage response facilitates uncontrolled cell proliferation with genomic instability and tumorigenesis in non-malignant cells.

Abbreviations: BrdUrd, bromodeoxyuridine; CP, cisplatin; H2O2, hydrogen peroxide; MEF, mouse embryo fibroblasts; mRNA, messenger RNA; PrEC, prostate epithelial cell; SA-β-gal, senescence-associated β-galactosidase; siRNA, small interfering RNA

Received June 6, 2007; revised August 2, 2007; accepted August 2, 2007.


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