Induction of EMT by Twist Proteins as a Collateral Effect of Tumor-Promoting Inactivation of Premature Senescence
Induction of MET by Twist Proteins as a Collateral Effect of Tumor-Promoting Inactivation of Premature Senescence
Ansieau, S. et al. Cancer Cell. 14, 79 – 89 (2008)
Speaker: Shi-Yu Chao (趙世宇) Time: 14:00~15:00, Nov. 12, 2008
Commentator: Dr. Pin Ling (凌斌老師) Place: Room 601
Abstract：
Oncogene-induced premature senescence is one of safeguard programs when cells receive abnormal growth signals from oncoproteins. Transformation of primary cells by ras oncogenes would induce cellular senescence that would result cell-cycle arrest and other senescence characteristics [1]. Twist proteins are the basic helix-loop-helix transcriptional factors that have important regulatory functions during embryogenesis and tumor metastasis [2]. In this paper, the authors discover that Twist proteins have the ability to abrogate oncogene-induced senescence, promote cell proliferation and lead to epithelial-mesenchymal transition (EMT). Analysis of Twist1 and Twist2 expression profiles in independent spontaneous mammary tumors from MMTV-ErbB2/Neu transgenic mice showed that the Twist2 gene was highly activated. Moreover, Twist1 and Twist2 genes were also overexpressed in several human primary tumor cells and cancer cell lines, especially in melanomas. Twist proteins cooperate with abnormally activated Ras (H-RasV12) to inhibit the transcription of p16INK4a and p21Cip1 that are key regulators in p53- and Rb-dependent pathways, and subsequently lead to abrogate oncogene-induced premature senescence. The cooperation between Twist proteins and H-RasV12 also promotes the cells undergoing EMT and invasiveness. Twist proteins-mediated EMT demonstrated the significant decrease of the E-cadherin epithelial marker and modest increase of the vimentin mesenchymal marker. And activated Ras has cooperative effect on promoting complete EMT. These findings suggest that Twist1 and Twist2 allow cancer cells to override premature senescence and cooperation of Twists with mitogenic protein promotes complete EMT, which facilitates invasion and metastasis of the cells.
References：
1. Serrano, M., Lin, A.W., McCurrach, M.E., Beach, D., and Lowe, S.W. (1997) Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell. 88, 593-602.
2. Yang, J., Mani, S.A., Donaher, J.L., Ramaswamy, S., Itzykson, R.A., Come, C., Savagner, P., Gitelman, I., Richardson, A., and Weinberg, R.A. (2004) Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell. 117, 927-939.