Notch3 functions as a tumor suppressor by controlling cellular senescence
Menée in vitro et sur des échantillons de cancer du sein et de mélanome, cette étude met en évidence un mécanisme par lequel, en régulant la sénescence cellulaire, la protéine Notch3 joue un role de suppresseur de tumeurs
Notch signaling regulates a broad spectrum of cell fate decisions and differentiation. Both oncogenic and tumor suppressor functions have been demonstrated for Notch signaling. However, little is known about the underlying mechanisms of its tumor suppressor function. Here we report that expression of Notch3, a member of Notch family transmembrane receptors, was elevated in human cells during senescence activated by various senescence-inducing stimuli. This up-regulation of Notch3 was required for the induction of p21 expression in senescent cells. Down-regulation of Notch3 led to a delayed onset of senescence and extended replicative lifespan, whereas adventitious expression of Notch3 was sufficient to activate senescence and p21 expression. The ability of Notch3 to induce senescence and p21 expression was dependent on the canonical Notch singling. Deletion of p21 in cells significantly attenuated Notch3-induced senescence. Furthermore, a significant decrease in Notch3 expression was observed in human tumor cell lines as well as primary human breast cancer and melanoma samples compared to normal tissues. Restoration of Notch3 expression in human tumor cells resulted in inhibition of cell proliferation and activation of senescence. Collectively, our results reveal a novel function of Notch3 in senescence regulation and tumor suppression.