p53 is a major tumor suppressor and a key component of DNA damage signaling that induces either cell cycle arrest or apoptosis. p53 also has a significant role in the induction of checkpoints in response to telomere shortening (Shay et al. 1991, Hara et al. 1991, Chin et al. 1999). According to the M1/M2 model of cell mortality, telomere dysfunction induces two checkpoints (mortality stages) limiting the proliferation of primary human cells (Wright and Shay 1992): Low levels of telomere dysfunction induce cell cycle arrest and replicative senescence; high levels of telomere dysfunction induce apoptosis. It has been shown that inhibition of p53

by viral oncogenes or dominant negative mutations can extend the life span of human cells by inhibiting the induction of senescence (Wright and Shay 1992, Bond et al. 1994). There is evidence that p53-independent pathways can limit the proliferation of cells in response to telomere dysfunction by inducing p16 (Bond et al. 2004; see Sharpless, this volume). Abrogation of both Rb- and p53-checkpoint function prevents the induction of senescence cell cycle arrest in response to telomere dysfunction (Wright and Shay 1992). However, cell proliferation beyond the M1 checkpoint results in further telomere shortening, eventually inducing the second mortality stage, M2. M2 is characterized by massive telomere shortening, chromosomal instability, and cell death (see Allsopp; see Rudolph, this volume). In agreement with this cell culture model, low levels of telomere dysfunction in mouse liver induced p53-dependent senescence, whereas high levels induced p53-independent apoptosis (Lechel et al. 2005).

Studies in telomerase-deficient mice have shown cell type specific differences in response to telomere dysfunction (Lee et al. 1998). Late-generation Terc mice show an impairment in organ homeostasis correlating with elevated rates of apoptosis in thymic lymphocytes and male germ line (Lee et al. 1998, Hemann et al. 2001a). In contrast, cell cycle arrest was the major checkpoint limiting liver regenerating in response to telomere shortening (Satyanarayana et al. 2003). In the intestine, an impairment in epithelia maintenance correlated with both cell cycle arrest and apoptosis in the basal crypts of intestinal epithelium, which carries the stem and progenitor cells (Choudhury et al. 2007).

The in vivo role of p53 in response to telomere shortening has been studied in mice doubly mutant for Terc and p53 (Chin et al. 1999). Deletion of p53 rescued germ cell apoptosis and testis atrophy in late-generation Terc mice (Chin et al. 1999). This resulted in increased fertility as observed in the propagation of telomere dysfunctional mice until the eighth generation as compared to the mice with intact p53, who became infertile in the sixth generation. Nevertheless, Terc -/-germ line atrophy and infertility reappeared in G7/8 mTerc -/-, p53 -/- mice, indicating that p53-independent checkpoints can limit germ cell maintenance in response to severe telomere dysfunction (Chin et al. 1999).

Deletion of p53 did not result in improved survival of telomere dysfunctional mice because of early tumor development in these mice (Artandi et al. 2000). Tumors in doubly mutant mice were characterized by high rates of chromosomal instability. Specifically Terc p53+/- mice exhibited a shift in the tumor spectrum toward a higher incidence of epithelial cancers (Artandi et al. 2000). These indicated that telomere dysfunction can cooperate with loss of p53 to induce chromosomal instability and cancer initiation. The tumor spectrum in Terc p53+/~ mice mimicked the high incidence of epithelial cancer in ageing humans, indicating that similar mechanisms might be involved in tumor initiation during human ageing (see Rudolph, this volume). The high incidence of cancer and early death of Terc p53 mice prevented study of the influence of p53 on organ maintenance and stem cell function in response to telomere shortening and ageing. There is experimental evidence that overactivation of p53 induces premature ageing in mice (Donehower 2002). Mice expressing a mutant, overactive form of p53 display premature ageing phenotypes such as reduced longevity, osteoporosis, generalized organ atrophy, and diminished stress tolerance (Tyner et al. 2002). Moreover, it has been shown that hypermorphic levels of p53 in these mice affect hematopoietic stem cell (HSC) number, proliferation, and _ functionality with age, whereas deletion of one copy of p53 increased HSC proliferation during mouse ageing (Dumble et al. 2007). In contrast, telomere dysfunctional mice carrying an extra copy of wild-type p53 gene under its natural promoter (total three copies of p53) did not show an increase in tissue atrophy or a shortening in life span (Garcia-Cao et al. 2006). These results were surprising since telomere dysfunctional mice carrying an extra copy of p53 are expected to have a 1.5-fold increase in p53 gene dosage when compared to telomere dysfunctional mice with only two copies of p53. Notably, the in vivo load of telomere-derived chromosomal damage was significantly decreased in super-p53/telomerase-null mice compared with normal-p53/telomerase-null mice, indicating that the removal of damaged cells may have prevented the acceleration of ageing phenotypes in these mice.

Together these data suggest that although p53 per se plays a role in stem cell function and organ maintenance, telomere-driven ageing can also act through p53-independent pathways. To this end, it remains an open question to delineate p53-dependent as well as p53- independent pathways controlling adult stem cell ageing in the context of dysfunctional telomeres and ageing.

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Are You Expecting? Find Out Everything You Need to Know About Pregnancy and Nutrition Without Having to Buy a Dictionary. This book is among the first books to be written with the expertise of a medical expert and from the viewpoint of the average, everyday, ordinary,

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