Role for autophagy in the establishment of senescence


Session type:

Andrew Young, Masako Narita, Manuela Ferreira, Kristina Kirschner, Fiona Watt, Masashi Narita

Cancer Research UK, Cambridge, UK


Role for autophagy in the establishment of senescence


Senescence is a permanent state of cell cycle arrest arising from various cellular stresses, such as oncogenic mutation. Accumulating evidence suggests that senescence is a bona fide tumour suppressor mechanism in vivo. Senescence is a complex phenotype, which involves multiple effector mechanisms. Here we investigate the involvement of the vesicular protein degradation process of autophagy in senescence.


We find that autophagy is upregulated concomitant with the establishment of oncogenic ras-induced senescence and indeed that autophagy is required for its efficient establishment. The PI3K pathway, a negative regulator of autophagy, is suppressed during ras-senescence through negative feedback. Consistently, the upregulation of autophagy is correlated with the suppression of the PI3K pathway during ras-senescence. We also find a similar autophagic phenotype in DNA damage-induced senescence. A specific subset of autophagy-related (atg) genes is upregulated upon oncogenic ras expression or DNA damage. Strikingly, the same subset of atg genes was found upregulated in murine papillomas, an in vivo senescence model, but not in normal skin nor squamous cell carcinomas. In addition, immunohistochemistry revealed a punctate LC3 staining, marking active autophagy, which was only found in those areas of the papillomas positive for senescence markers but negative for proliferation markers.


Our results identify stress-induced autophagy to be a new effector mechanism of senescence.