Annuaire
Vincent GELI, CRCM Marseille
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Le 14/12/2018, de 11:00 à 12:00 |
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| S'adresser à | Equipe Palladino - Salle Condorcet (1 place de l'école) |
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Of the stresses that trigger cellular senescence, unrelenting telomere shortening plays a particularly important role because this serves as a "biological clock" that regulates the lifespan. The "clock" starts ticking when telomerase is shut down before birth in most somatic tissues. A key regulator of cellular arrest in response to telomere shortening is the cyclin-dependent kinase inhibitor p21. p53-dependent upregulation of p21 is thought to be the primary event inducing replicative senescence. We asked whether aging can be delayed by abrogating telomere shortening in senescent cells by expressing telomerase "only when it is needed" and what would be the consequences of this conditional ectopic expression of telomerase. Indeed, previous studies revealed that overexpression of telomerase promotes cell proliferation and inflammation independently of its activity at telomeres. To this purpose, we have created a knock-in mouse model in which a cassette encoding mCherry-2A-mTert (telomerase) has been inserted after the first exon of p21 (p21-mTert mouse). Our results indicate that expression of telomerase driven by the p21Cdk1a promoter decreases the number of senescent cells in the lung parenchyma and prevents emphysema, either in old mice or in mice experiencing hypoxia. Collectively, our results indicate that p21-mTert mice are protected from lung dysfunction related to cellular senescence. Strikingly, we also observed unexpected phenotypes associated to this ectopic telomerase expression. Indeed, p21-mTert mice exhibit a gradual increase in body weight, exhibited white fat accumulation, liver dysfunction, steatosis, and hepatocarcinoma. Moreover, p21-mTert mice show clear defects in vascular patterning. The phenotypes exhibited by the p21-mTert mice make this mouse model a very attractive model to understand the canonical and the non canonical role of telomerase.
Contact : Francesca Palladino