Mallette Frédérick A, Gaumont-Leclerc Marie-France, Ferbeyre Gerardo
Département de Biochimie, Université de Montréal, Montréal, Québec H3C 3J7, Canada.
Genes Dev. 2007 Jan 1;21(1):43-8. doi: 10.1101/gad.1487307.
Here we report that RNA interference against ATM inhibited p53 accumulation in cells expressing oncogenic STAT5 and cooperated with Rb inactivation to suppress STAT5A-induced senescence. Knocking down ATM was also effective to bypass E2F1-induced senescence and in combination with Rb inactivation, inhibited RasV12-induced senescence. Cells that senesced in response to ca-STAT5A or RasV12 accumulated DNA damage foci and activated ATM, ATR, Chk1, and Chk2, indicating that aberrant oncogene activation induces a DNA damage signaling response. Intriguingly, bypassing oncogene-induced senescence by inactivation of p53 and Rb did not eliminate the accumulation of oncogene-induced DNA damage foci (ODDI), suggesting a mechanism that may limit transformation in immortalized cells.
在此我们报告，针对ATM的RNA干扰在表达致癌性STAT5的细胞中抑制了p53的积累，并与Rb失活协同作用以抑制STAT5A诱导的衰老。敲低ATM对于绕过E2F1诱导的衰老也有效，并且与Rb失活相结合，抑制了RasV12诱导的衰老。响应于ca-STAT5A或RasV12而衰老的细胞积累了DNA损伤灶并激活了ATM、ATR、Chk1和Chk2，表明异常的癌基因激活诱导了DNA损伤信号反应。有趣的是，通过p53和Rb失活绕过癌基因诱导的衰老并未消除癌基因诱导的DNA损伤灶（ODDI）的积累，这提示了一种可能限制永生化细胞转化的机制。
