A negative feedback signaling network underlies oncogene-induced senescence

Speaker: 賴曉菁                                                    Date:14:10~15:00, April 18, 2007

Commentator: 楊倍昌 老師                                 Place: Room: 601

Cellular senescence is an irreversible cell-cycle arrest. Senescent cells stop synthesizing DNA and lost their capacity to divide. Another feature of senescent cell is the increased activity of the senescence-associated β-galactosidase (SA-β-gal), which is used to detect senescent cells. Ras can induce cellular senescence and may limit tumor development in some benign lesions. In this study, the authors found that in human fibroblast, the deficiency of Ras GTPase activating protein, NF-1, can induce cellular senescence, but in mouse embryonic fibroblast, NF1-deficiency did not induce senescence and the cells became immortalized. Both human and mouse fibroblast cells contain the normal p53 response; indicating that the same genetic event can trigger dramatically different biological responses in different cells. NF-1 deficiency caused the rapid decrease of the activity of Ras and its effectors, and overexpression of activated Raf can induce the same phenomenon, indicating that NF1 deficiency, Raf and Ras induce a global negative feedback signaling pathway. Furthermore, some proteins known to suppress Ras, like Sprouty and RasGAPgenes, were upregulated when Raf was activated. These genes may partial involved the feedback signaling pathway. All together, while Ras was aberrantly activated, a negative feedback signaling network was induced to suppress oncogenic signal and to trigger cellular senescence.

References:

1.      Courtois-Cox S., Genther Wiliams SM, Reczek EE., Jounson BW., McGilicuddy LT, Johannessen CM, Hollstein PE, MacCollin M, Cichowski, K. (2006). A negative feedback signaling network underlies oncogene-induces senescence. Cancer Cell 10. 459-472.

2.      Schmitt CA. (2007). Cellular senescence and cancer treatment. Biochim Biophys Acta 1775. 5-20.