Larsson: Cellular senescence–an integrated perspective apoptosis; so why is senescence the outcome of telomere instability? The first thing to point out is that there is little evidence of senescence in human tissues, so far senescent cells have only been detected in skin of elderly people (Dimri et al, 1995), a finding that could not be repeated (Severino et al, 2000). One obvious mechanism that could regulate the choice between senescence and apoptosis is if the apoptotic process was inhibited and senescence occurred instead as a default mechanism. The mitochondrial antiapoptotic protein Bcl-2 has been proposed to represent such a mechanism. Unexpectedly, overexpression of Bcl-2 has been shown to induce senescence, judged by SA!GAL staining, yet this may more resemble quiescence as p27 was overexpressed (Crescenzi et al, 2003). Bcl-2 can also accelerate RAS-induced senescence to some extent (Tombor et al, 2003). In support of the hypothesis, Bcl-2 has been described to shift the response from apoptosis to senescence when artificially overexpressed in rat cells (Rincheval et al, 2002). In the report describing a shift from apoptosis to senescence upon Bcl-2 overexpression, p21 was found to be overexpressed. In fact, this could be the reason for the shift from apoptosis to senescence as p21 expression after DNA damage lead to senescence while absence of p21 induction after DNA damage lead to apoptosis (Seoane et al, 2002). Similarly, apoptosis was associated with low p21 levels whereas senescence was associated with high p21 levels in a cancer cells treated with interferon-$ (Detjen et al, 2003). If p21 decides if the response, downstream of p53induction, will be senescence or apoptosis, then an important question is why p53 sometimes induces p21 expression and sometimes not. Some of the regulation could be a result of the convergence of several pathways that directly regulate p21. For example both Miz-1 and CUGBP have been described to affect the transcription and translation of p21 respectively (Iakova et al, 2004; Seoane et al, 2002). It is also possible that the decision, of whether or not to induce p21, occurs at the level of p53 activation. Interestingly, the phosphorylation patterns of p53 during induction of senescence and after a DNA damage treatment leading to apoptosis seems to differ (Chehab et al, 1999; Webley et al, 2000). The question would then be what regulates the differential phosphorylation of p53 during senescence and apoptosis. Interestingly, there are some indications of how this could be achieved. It appears that a large DNA damage response leads to apoptosis while a low but persistent activation of p53 induces senescence. For example, upon hydrogen peroxide treatment both senescence and apoptosis are possible outcomes; apoptosis was associated with higher levels of p53 and low levels of p21 while senescence was associated with lower levels of p53 and higher levels of p21 (Chen et al, 2000). Similarly a TRF2 mutant that cause telomere dysfunction induced apoptosis or senescence, depending on the expression level and thereby the extent of telomere damage (Lechel et al, 2005); and substantial overexpression of p53 induced apoptosis while lower overexpression induced senescence (Macip et al, 2003). In summary, it seems like p21 and the nature of the p53 response is the major determinant whether the p53 response will induce apoptosis or
senescence. The differential regulation of p21 needs to be further clarified.
Acknowledgements I would like to thank Dr James A Timmons, Dr Christina Karlsson-Rosenthal and Dr Claes Wahlestedt for reading the manuscript.
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