Oncogenes and senescence: breaking down in the fast lane
- Michael T. Hemann1,3 and
- Masashi Narita2,4
- 1 Center for Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA;
- 2 Cancer Research United Kingdom, Cambridge Research Institute, Cambridge CB2 0RE, United Kingdom
This extract was created in the absence of an abstract.
Aberrant oncogene expression is the driving force behind the development of all cancers. Consequently, robust tumor suppressive processes have evolved in multicellular organisms to recognize and counteract the malignant potential of individual cells harboring deregulated oncogenes. These processes prevent tumor development by directing cells with inappropriate proliferative signals toward distinct terminal states, including cell death and an irreversible form of cell cycle arrest called cellular senescence (Lowe et al. 2004). While much of the cellular machinery that executes these tumor suppressive functions is known, the “oncogenic signals” that engage this machinery are less understood. In this issue of Genes & Development, Ferbeyre and colleagues (Mallette et al. 2007) provide new insight into this process, implicating oncogene-induced DNA damage signaling as a critical instigator of oncogene-induced senescence.
DNA damage as an oncogenic signal
The overexpression or activation of growth-promoting genes is essential for cancer development, yet normal cells are hard-wired to recognize inappropriate proliferative signals. This cellular sensitivity to oncogenes was first recognized in cells engineered to overexpress c-Myc or the viral oncogene E1A. While these “immortalized” oncogene-expressing cells grew more rapidly, they also became exquisitely sensitive to cell death stimuli and failed to transform (Evan et al. 1992; Lowe and Ruley 1993). Thus, oncogene overexpression could concurrently promote cell growth and cell death. Subsequently, experiments using an activated variant of the Ras oncoprotein showed that mutant Ras also failed to transform normal cells. Rather, enforced Ras expression induced a transient increase in cell proliferation followed by a stable cell cycle arrest termed cellular senescence (Serrano et al. 1997).
While senescence and apoptosis represent dramatically different cellular responses to deregulated oncogene expression, they can be initiated through the activation of a common tumor suppressor network. Specifically, studies in primary murine fibroblasts have convincingly shown that the induction of the tumor suppressor p53 and …
