Molecular Mechanisms of Tumor Suppression in Response to Telomere Shortening

A current concept indicates that DNA damage checkpoints impair cell proliferation in response to telomere dysfunction thereby suppressing tumor formation. In agreement with this model, inactivation of the p53 and/or Rb pathways allows human fibroblast to bypass the M1-senescent checkpoint (Wright and Shay 1992, Gire and Wynford-Thomas 1998; see also Allsopp, this volume; Gutierrez and Ju, this volume). In addition, there is a second mortality stage (M2) that limits survival of cells that bypassed senescence. M2 is characterized by very short telomeres, high levels of CIN, and massive cell death. This stage has therefore been called crisis (Wright and Shay 1992). The crisis checkpoint is much less defined than the senescence checkpoint. Both crisis and senescence represent potent barriers protecting the organisms against cancer. Vice versa, defects in these checkpoints may allow proliferation of cells with critically short telomeres and could cooperate with telomere dysfunction during initiation of CIN and cancer.

In agreement with this concept, p53 deletion cooperates with telomere dysfunction to induce chromosomal instability and initiation of epithelial cancer in ageing telomerase knockout mice (Artandi et al. 2000; see above). However, the cooperation between loss of DNA damage checkpoints and telomere dysfunction appears to be more complex and needs to be further elucidated. In contrast to p53 deletion, the deletion of ATM does not lead to an increase in cancer formation in mTERC-/- mice but accelerated ageing in the double mutant mice (Wong et al. 2003). These data indicate that ATM-independent mechanisms can activate checkpoints in response to telomere dysfunction possibly involving ATR, which has been implicated in replicative senescence of human fibroblasts (d'Adda di Fagagna et al. 2003). In addition, the data suggest that loss of ATM may increases DNA damage in telomere dysfunctional mice, thus accelerating ageing phenotypes.

It is possible that the role of ATM in telomere capping (Verdun and Karlseder 2006) or detoxification of reactive oxygen species (Barlow et al. 1999) is responsible for increased DNA/telomere damage and accelerated ageing of mTERC-/-, ATM-/- double mutant mice.

In contrast to ATM deletion, the knockout of p21 rescues premature ageing and life span of mTERC-/- mice (Choudhury et al. 2007). p21 is one of the primary targets of p53-inducing senescence of human cells in response to telomere dysfunction (Brown et al. 1997). Notably, p21 deletion did not increase the rate of cancer formation in ageing mTERC-/- mice. A possible explanation is that p21 deletion rescues cell cycle arrest and stem cell depletion in mTERC-/- mice but leaves apoptosis checkpoints intact (Choudhury et al. 2007). Apoptosis checkpoints could remove genetically instable cells with high rates of CIN, thus preventing the accumulation of CIN and cancer initiation in p21-/-, TERC-/- mice. In agreement with this hypothesis, the inhibition of p53-dependent apoptosis in p53 mutant mice leads to an increase of cancer (Cosme-Blanco et al. 2007). However, when apoptosis-deficient, p53 mutant mice were crossed with mTERC-/- mice tumor induction was impaired, correlating with a strong activation of p21 and senescence associated P -galactosidase in mouse tissues (Cosme-Blanco et al. 2007; see also Chang, this volume). Together, these data suggest that both pathways, p53-dependent apoptosis and p53-dependent cell cycle arrest, can compensate each other to suppress tumor formation in response to telomere dysfunction (Fig. 11.3).

Telomere Shortening

Telomere Dysfunction p53-dependent Checkpoints Cell Cycle Arrest (p21) Apoptosis (Puma, Bax)

Fig. 11.3 Telomere shortening suppresses tumor progression: (i) Telomere dysfunction induces p53-dependent checkpoints Limiting cell proliferation (p21) and this checkpoint could also involve p53 target genes including apoptosis (PUMA, Bax); (ii) In addition, telomere dysfunction can limit cell survival by inducing p53-independent checkpoints. The nature of these checkpoints remains to be analyzed but could involve mitotic checkpoints or ploidy checkpoints. (iii) Telomere dysfunction and the activation of checkpoint responses induce chromatin modification and the activation of the Rb-checkpoint leading to cell cycle arrest

Fig. 11.3 Telomere shortening suppresses tumor progression: (i) Telomere dysfunction induces p53-dependent checkpoints Limiting cell proliferation (p21) and this checkpoint could also involve p53 target genes including apoptosis (PUMA, Bax); (ii) In addition, telomere dysfunction can limit cell survival by inducing p53-independent checkpoints. The nature of these checkpoints remains to be analyzed but could involve mitotic checkpoints or ploidy checkpoints. (iii) Telomere dysfunction and the activation of checkpoint responses induce chromatin modification and the activation of the Rb-checkpoint leading to cell cycle arrest

In agreement with the pivotal role of p53 in human carcinogenesis, tumor suppression in telomere-dysfunctional mice is associated with an activation of p53 in tumor cells as well as with increased rates of tumor cell apoptosis and impaired tumor cell proliferation (Rudolph et al. 2001). In addition, there is emerging evidence that p53-independent checkpoints can impair cancer formation in response to telomere dysfunction and chromosomal instability in vivo. Acute induction of telomere dysfunction by inhibition of the telomere-binding protein TRF2 leads to p53-independent apoptosis in liver cells of p53-/- mice (Lechel et al. 2005). In addition, p53-independent checkpoints impair proliferation and induce apoptosis in p53-/- tumors with dysfunctional telomeres (Lechel et al. 2007). These findings are in line with the observation that two checkpoints (M1 and M2) can limit proliferation of primary human cells in response to telomere shortening. In human fibrob-lasts the senescence checkpoint is p53-dependent, but the crisis checkpoint is p53-independent (Wright and Shay 1992; see also Allsopp, this volume). While the above studies have provided experimental evidence that p53-independent checkpoints can impair tumor progression in mouse models, the molecular components of this checkpoint and its relevance to human carcinogenesis need to be explored in greater detail. Studies in mice and human cells have shown that the activation of p53-independent checkpoints in response to telomere dysfunction correlates with the accumulation of DNA damage and the evolution of massive chromosomal instability (Wright and Shay 1992, Lechel et al. 2007, Fig. 11.3), suggesting that these checkpoints involve DNA damage signaling and ploidy checkpoints.

Detoxification and Weight Loss

Detoxification and Weight Loss

Detoxification is something that is very important to the body, but it is something that isn't understood well. Centuries ago, health masters in the East understood the importance of balancing and detoxifying the body. It's something that Western medicine is only beginning to understand.

Get My Free Ebook


Post a comment