title: Notch3 functions as a tumor suppressor by controlling cellular senescence.
abstract: Notch signaling regulates a broad spectrum of cell fate decisions and differentiation. Both oncogenic and tumor suppressor functions have been shown 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 upregulation of Notch3 was required for the induction of p21 expression in senescent cells. Downregulation 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 with 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.
authors.affiliation: Departments of Cell and Developmental Biology and Information Service Research Computing Group, University of Massachusetts Medical School, Worcester, MA 01655, USA .
authors.forename: Hang
authors.initials: H
authors.lastname: Cui
authors.forename: Yahui
authors.initials: Y
authors.lastname: Kong
authors.forename: Mei
authors.initials: M
authors.lastname: Xu
authors.forename: Hong
authors.initials: H
authors.lastname: Zhang
mesh_terms: D002454:Cell Differentiation / Q000502:physiology; D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000502:physiology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis / Q000235:genetics; D016147:Genes, Tumor Suppressor; D006801:Humans; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D000071656:Receptor, Notch3; D051880:Receptors, Notch / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D015533:Transcriptional Activation
chemical_list: C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; C499374:NOTCH3 protein, human; D000071656:Receptor, Notch3; D051880:Receptors, Notch