6. Cellular Senescence 

 

The limitation of maximal primary human cells proliferation capacity in vitro was stated as “cellular senescence” (Hayflick L and Moorhead P S., 1961 as cited in Loo T M et al., 2019) (Loo T M et al., 2019). This process in turn defined as “replicative senescence” as the restriction in proliferation limit occurs as a result of telomere shortening (Loo T M et al., 2019).

 

Cellular senescence is known to be a critical mechanism of tumor repression as it occurs when cell cycle arrest takes place irretrievably and the proliferation of the impaired cells is barred, which ultimately decreases the possibility of cancer (Campisi J., 2013) (Munoz-Espin D and Serrano M., 2014) (Loo T M et al., 2019). 

 

Activation of senescent cell cycle arrest occurs as retinoblastoma protein and therefore expression of E2F target gene are hindered as a result of activities of inhibitors p16 INK4a (inhibiting the cyclin D-CDK4/6 complex) and p21 WAF1/CIP1 (hindering cyclin E-CDK2 function). Furthermore, expressional activation of CDK (cyclin-dependent kinase) inhibitors, p16 INK4a and p16 INK4a , are caused as cellular senescence taking place as a result of continuous DNA damage response in normal cells. (Bartkova J et al., 2006 as cited in Loo T M et al., 2019) (Di Micco R et al., 2006 as cited in Loo T M et al., 2019) (Ohtani N et al., 2001 as cited in Loo T M et al., 2019) (Brugarolas J et al., 1995 as cited in Loo T M et al., 2019) (Maehara K et al., 2005) (Takahashi A et al., 2006 as cited in Loo T M et al., 2019 ) (Imai Y et al., 2014) (Loo T M et al., 2019).

 

Cellular Senescence References

1.        Bartkova, J. et al. Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints. Nature 444, 633–637 (2006).

2.        Brugarolas, J. et al. Radiation-induced cell cycle arrest compromised by p21 deficiency. Nature 377, 552–557 (1995).

3.        Campisi, J. Aging, Cellular Senescence, and Cancer. Annu. Rev. Physiol. 75, 685–705 (2013).

4.        Di Micco, R. et al. Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication. Nature 444, 638–642 (2006).

5.        Hayflick, L. & Moorhead, P. S. The serial cultivation of human diploid cell strains. Exp. Cell Res. 25, 585–621 (1961).

6.        Imai, Y. et al. Crosstalk between the Rb Pathway and AKT Signaling Forms a Quiescence-Senescence Switch. Cell Rep. 7, 194–207 (2014).

7.        Loo, T. M., Miyata, K., Tanaka, Y. & Takahashi, A. Cellular senescence and senescence‐associated secretory phenotype via the cGAS‐STING signaling pathway in cancer. Cancer Sci. 111, 304–311 (2020).

8.        Ohtani, N. et al. Opposing effects of Ets and Id proteins on p16INK4a expression during cellular senescence. Nature 409, 1067–1070 (2001).

9.        Takahashi, A. et al. Mitogenic signalling and the p16INK4a–Rb pathway cooperate to enforce irreversible cellular senescence. Nat. Cell Biol. 8, 1291–1297 (2006).