title: Attenuation of TORC1 signaling delays replicative and oncogenic RAS-induced senescence.
abstract: Numerous stimuli, including oncogenic signaling, DNA damage or eroded telomeres trigger proliferative arrest, termed cellular senescence. Accumulating evidence suggests that cellular senescence is a potent barrier to tumorigenesis in vivo, however oncogene induced senescence can also promote cellular transformation. Several oncogenes, whose overexpression results in cellular senescence, converge on the TOR (target of rapamycin) pathway. We therefore examined whether attenuation of TOR results in delay or reversal of cellular senescence. By using primary human fibroblasts undergoing either replicative or oncogenic RAS-induced senescence, we demonstrated that senescence can be delayed, and some aspects of senescence can be reversed by inhibition of TOR, using either the TOR inhibitor rapamycin or by depletion of TORC1 (TOR Complex 1). Depletion of TORC2 fails to affect the course of replicative or RAS-induced senescence. Overexpression of REDD1 (Regulated in DNA Damage Response and Development), a negative regulator of TORC1, delays the onset of replicative senescence. These results indicate that TORC1 is an integral component of the signaling pathway that mediates cellular senescence.
authors.affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA, USA. marinak@scripps.edu
authors.forename: Marina
authors.initials: M
authors.lastname: Kolesnichenko
authors.forename: Lixin
authors.initials: L
authors.lastname: Hong
authors.forename: Rong
authors.initials: R
authors.lastname: Liao
authors.forename: Peter K
authors.initials: PK
authors.lastname: Vogt
authors.forename: Peiqing
authors.initials: P
authors.lastname: Sun
mesh_terms: D002478:Cells, Cultured; D016922:Cellular Senescence / Q000187:drug effects*; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D018631:ras Proteins / Q000378:metabolism*
chemical_list: C500984:CRTC1 protein, human; C469991:DDIT4 protein, human; D034741:RNA, Small Interfering; D014157:Transcription Factors; D018631:ras Proteins; D020123:Sirolimus