Journal Article

Role of p14<sup>ARF</sup> in TWIST-mediated senescence in prostate epithelial cells

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

in Carcinogenesis

Volume 28, issue 12, pages 2467-2475
Published in print December 2007 | ISSN: 0143-3334
Published online August 2007 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgm185
Role of p14ARF in TWIST-mediated senescence in prostate epithelial cells

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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.

Journal Article.  5083 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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