The DNA damage signaling pathway is a critical mediator of oncogene-induced senescence
Abstract
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.
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Footnotes
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↵1 Corresponding author.
↵1 E-MAIL g.ferbeyre{at}umontreal.ca; FAX (514) 343-2210.
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Supplemental material is available at http://www.genesdev.org.
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Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.1487307
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- Received August 29, 2006.
- Accepted November 15, 2006.
- Copyright © 2007, Cold Spring Harbor Laboratory Press