The social and economic impact of an ageing population is a worrying concern our developed countries are facing, as well as Jess developed countries. Therefore, there is a real necessity to develop nove! approaches to better understand the ageing process and to prevent age-related diseases. Cellular senescence, a predominant hallmark of ageing of mitotic tissues, can be related to proliferative potential exhaustion, oncogene activation or stress exposure. Moreover, emerging evidence indicates that cellular senescence is involved in the promotion of tissue repair and tumor suppression. In our study, we studied normal human keratinocytes (NHK.s) in replicative senescence or in UVB-stress induced premature senescence (UVB-SIPS). First, we compared different biomarkers of senescence in both senescent models including morphological changes and senescence-associated P-galactosidase activity (SA-pgal). Then we analysed the expression and secretion of three major SASP (Senescence Associated Secretory Phenotype) factors. We showed an increased secretion of IL(lnterleukin)-6 and -8, and a decreased secretion of VEGF (Vascular endothelial growth factor). We then investigated different molecular pathways. First, we studied the DNA Damage Response (DDR) pathway, and our results showed an activation of the ATM-Chk2-p53 pathway. Then we looked for the oxidative stress and we demonstrated an increased generation of reactive oxygen species (ROS) including superoxide anions after UVB exposures .. We finally studied Nrf2 activation and the expression of Nrf2-dependent antioxidant genes. Our data allow us to clarify the active pathways following UVB stresses that are potentially involved in the appearance of the senescent phenotype.
|la date de réponse||2017|
|Superviseur||Florence Chainiaux Debacq (Promoteur)|