What Induces p16INK4a with Ageing

Given these results, the regulation of the INK4a/ARF locus becomes a crucial question. In particular, a knowledge of what induces p16INK4a with ageing would in turn suggest the true molecular causes of why stem cells fail with age. The stimuli that activate these senescence-promoting pathways with ageing are not clearly elucidated and likely differ among species and tissue type (Fig. 9.4). Clearly, a wide variety of noxious stimuli induce p16INK4a in humans and mice, including ionizing radiation, reactive oxygen species, telomere dysfunction, and replicative stress (reviewed in Kim and Sharpless 2006, von Zglinicki et al. 2005). While Arf expression with ageing closely mirrors that of p16INK4a in rodents, in humans, ARF expression does not appear to increase as markedly. The molecular pathways that activate the INK4a/ARF locus in response to such stresses are less well understood, although roles for E2F (Aslanian et al. 2004, DeGregori et al. 1997, Kotake et al. 2007) and MAP kinase signaling ERK and p38 (Bulavin et al. 2004, Satyanarayana et al. 2004, Wang et al. 2002, Zhu et al. 1998) have been suggested, the latter possibly

Fig. 9.4 Senescence and ageing. Diverse cellular stresses, including but not limited to telomere dysfunction and other forms of DNA damage, increase with age, inducing the senescence-promoting effects of p16INK4a and p53. The PcG complexes appear to repress Ink4a/Arf activation and thereby modulate stem cell function, although to date, no direct proof has established a reduction in PcG activity with ageing. With ageing, activation of p16INK4a is associated with the appearance of hypofunctional or senescent, formerly self-renewing cells (illustrated as blue cells with red SAHF) (See Color Plate)

Fig. 9.4 Senescence and ageing. Diverse cellular stresses, including but not limited to telomere dysfunction and other forms of DNA damage, increase with age, inducing the senescence-promoting effects of p16INK4a and p53. The PcG complexes appear to repress Ink4a/Arf activation and thereby modulate stem cell function, although to date, no direct proof has established a reduction in PcG activity with ageing. With ageing, activation of p16INK4a is associated with the appearance of hypofunctional or senescent, formerly self-renewing cells (illustrated as blue cells with red SAHF) (See Color Plate)

through a direct transcriptional effect of Ets transcription factors (Huot et al. 2002, Ohtani et al. 2001). A possible role for Polycomb Group complexes (PcG) with Ink4a/Arf regulation with ageing deserves particular consideration.

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