Necdin modulates proliferative cell survival of human cells in response to radiation-induced genotoxic stress
1 Centre de recherche du Centre hospitalier de l’Université de Montréal (CRCHUM), Institut du cancer de Montréal, Y-4606, 1560, rue Sherbrooke Est, Montréal, QC, H2L 4 M1, Canada
2 Département de Radiologie, Radio-oncologie et médecine nucléaire, Université de Montréal, Montréal, QC, H3C 3J7, Canada
3 Département de médecine, Université de Montréal, Montreal, QC, H3C 3J7, Canada
BMC Cancer 2012, 12:234 doi:10.1186/1471-2407-12-234Published: 12 June 2012
The finite replicative lifespan of cells, termed cellular senescence, has been proposed as a protective mechanism against the proliferation of oncogenically damaged cells, that fuel cancer. This concept is further supported by the induction of premature senescence, a process which is activated when an oncogene is expressed in normal primary cells as well as following intense genotoxic stresses. Thus, deregulation of genes that control this process, like the tumor suppressor p53, may contribute to promoting cancer by allowing cells to bypass senescence. A better understanding of the genes that contribute to the establishment of senescence is therefore warranted. Necdin interacts with p53 and is also a p53 target gene, although the importance of Necdin in the p53 response is not clearly understood.
In this study, we first investigated Necdin protein expression during replicative senescence and premature senescence induced by gamma irradiation and by the overexpression of oncogenic RasV12. Gain and loss of function experiments were used to evaluate the contribution of Necdin during the senescence process.
Necdin expression declined during replicative aging of IMR90 primary human fibroblasts or following induction of premature senescence. Decrease in Necdin expression seemed to be a consequence of the establishment of senescence since the depletion of Necdin in human cells did not induce a senescence-like growth arrest nor a flat morphology or SA-β-galactosidase activity normally associated with senescence. Similarly, overexpression of Necdin did not affect the life span of IMR90 cells. However, we demonstrate that in normal human cells, Necdin expression mimicked the effect of p53 inactivation by increasing radioresistance.
This result suggests that Necdin potentially attenuate p53 signaling in response to genotoxic stress in human cells and supports similar results describing an inhibitory function of Necdin over p53-dependent growth arrest in mice.