Role of p14ARF in TWIST-mediated senescence in prostate epithelial cells.
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 p14(ARF) 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 p14(ARF), 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.
Kwok
Wai Kei
WK
Department of Anatomy.
Ling
Ming-Tat
MT
Yuen
Hiu Fung
HF
Wong
Yong-Chuan
YC
Wang
Xianghong
X
D002460:Cell Line; D049109:Cell Proliferation; D016922:Cellular Senescence / Q000502:physiology*; D000071877:Checkpoint Kinase 1; D064447:Checkpoint Kinase 2; D004249:DNA Damage / Q000502:physiology; D004847:Epithelial Cells / Q000502:physiology*; D006801:Humans; D008297:Male; D009687:Nuclear Proteins / Q000502:physiology*; D011467:Prostate / Q000166:cytology*; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D025803:Tumor Suppressor Protein p14ARF / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D051879:Twist-Related Protein 1 / Q000502:physiology*
D009687:Nuclear Proteins; C495901:TP53 protein, human; C103173:TWIST1 protein, human; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53; D051879:Twist-Related Protein 1; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D011494:Protein Kinases; D064447:Checkpoint Kinase 2; C000605867:CHEK1 protein, human; C578634:CHEK2 protein, human; D000071877:Checkpoint Kinase 1; D017346:Protein Serine-Threonine Kinases