P21

Cdknla (p21) represents one of the first identified downstream targets of p53 mediating p53-dependent cell cycle arrest (El-Diery et al. 1993). In primary human fibroblasts p21 induces cell cycle arrest at the senescence stage in response to telomere dysfunction, whereas p21 deletion leads to an increased life span of these cells (Brown et al. 1997). In contrast to the well-established role of p21 in cellular senescence in cell culture, its role for in vivo ageing remains unclear. An increase in p21 expression occurs during human and rodent ageing in muscle (Edwards et al. 2007, Welle et al. 2004) and muscle stem cells (Machida and Booth 2004). p21 expression has also been observed in some age-associated diseases such as atherosclerosis (Matthews et al. 2006) and tubular fibrosis of the kidney (Ding et al. 2001). In contrast, heart myocytes of ageing mouse showed a decrease in p21 expression during ageing (Torella et al. 2004). Similarly, p21 expression is decreased in aging rat liver (Kitano et al. 1996). Based on the senescence marker SA-ßGal some studies have described an accumulation of senescent cells in aged skin of baboons (Herbig et al. 2006) as well as in human skin (Dimri et al. 1995). SA-ßGal-positive cells were also detected in atherosclerotic plaques (for review see Minamino and Komuro 2007) and liver cirrhosis (Wiemann et al. 2002). Together, these data indicate that p21 expression and senescence could contribute to tissue pathology during ageing and chronic disease in some tissues.

Studies in telomerase-deficient mice revealed a functional role of p21 on in vivo aging in the context of telomere dysfunction. p21 deletion had no influence on ageing and life span of Terc +/- mice with functional telomeres but significantly elongated the life span of Terc mice with dysfunctional telomeres (Choudhury et al. 2007). Increased life span of the Terc mice correlated with improved organ maintenance specifically observed in the intestinal epithelia and lymphocyte compartment. Notably, p21 deletion rescued the depletion of stem and progenitor cells in the gut and the hematopoietic system of ageing Terc mice, indicating that p21-dependent checkpoints limit stem cell self-renewal in these organs in response to telomere dysfunction. Moreover, p21 deletion improved the function of HSCs from Terc mice when tested in transplantation experiments.

Deletion of p21 rescued cell cycle arrest in intestinal stem and progenitor cells of telomere dysfunctional mice but did not prevent the induction of apoptosis in this compartment. Similarly, p21 deletion did not rescue germ cell apoptosis and testicular atrophy in Terc mice. In the hematopoietic system, p21 deletion prevented the depletion of the HSC compartment (lineage negative cells, Sca1+, c-Kit+ =LSK cells). This rescue was not associated with increased proliferation or suppression of apoptosis. Instead, there was evidence that p21 deletion prevented the induction of stem cell differentiation reducing the HSC pool size in Terc mice. Together, these results provided the first experimental evidence that inhibition of DNA-damage checkpoints can improve the maintenance and function of adult stem cells and organismal survival in the context of telomere dysfunction. Notably, SA-P-Gal staining did not reveal a strong accumulation of senescent cells in ageing Terc -/-, p21+'+ compared to Terc -/-, p21 -/- mice. These data indicate that p21-arrested cells may not persist indefinitely in aged tissues but might be removed by secondary mechanisms possibly involving apoptosis (Choudhury et al. 2007) or immune responses targeting senescent cells (Xue et al. 2007).

In contrast to the findings on p21 deletion in Terc -/- mice, deletion of p21 itself can also have negative effects on stem cell maintenance in telomerase wild-type mice with long telomere reserves. It has been reported that deletion of p21 leads to increased rates of HSC turnover (Cheng et al. 2000) and increased neuronal stem cell proliferation after ischemic injury (Qiu et al. 2004) in certain mouse strains. Increased rates of stem cell turnover resulted in depletion of HSCs when the animals were exposed to chemotherapy or under replication stress by repeated bone marrow transplantation (Cheng et al. 2000). Together, these findings suggest that p21 has a dual role in stem cell aging. On one hand, p21 appears to be important to maintain stem cell quiescence thus preventing stem cell exhaustion during ageing and in response to acute stress. On the other hand, p21 upregulation becomes disadvantageous in the context of telomere dysfunction in old mice, leading to depletion of stem and progenitor cell compartments by induction of cell cycle arrest or differentiation (for review see Ju et al. 2007a).

Notably, p21 deletion improved stem cell function, organ homeostasis, and life span of telomere-dysfunctional mice without accelerating cancer formation (Choudhury et al. 2007). Similarly, there was no evidence for an increase in genomic instability in bone marrow cells of Terc -/-, p21-/- mice compared to

Terc p21 +/+ mice. These data indicate that p21-independent checkpoints can prevent the accumulation of chromosomal instability and the initiation of cancer in telomere-dysfunctional mice (see Rudolph, this volume).

In conclusion, p21 might be considered as a potential therapeutic target to improve regeneration and organ homeostasis in chronic diseases and aging-related disorders associated with telomere dysfunction and reduced survival.

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