title: Tumor suppressor activity of the ERK/MAPK pathway by promoting selective protein degradation.
abstract: Constitutive activation of growth factor signaling pathways paradoxically triggers a cell cycle arrest known as cellular senescence. In primary cells expressing oncogenic ras, this mechanism effectively prevents cell transformation. Surprisingly, attenuation of ERK/MAP kinase signaling by genetic inactivation of Erk2, RNAi-mediated knockdown of ERK1 or ERK2, or MEK inhibitors prevented the activation of the senescence mechanism, allowing oncogenic ras to transform primary cells. Mechanistically, ERK-mediated senescence involved the proteasome-dependent degradation of proteins required for cell cycle progression, mitochondrial functions, cell migration, RNA metabolism, and cell signaling. This senescence-associated protein degradation (SAPD) was observed not only in cells expressing ectopic ras, but also in cells that senesced due to short telomeres. Individual RNAi-mediated inactivation of SAPD targets was sufficient to restore senescence in cells transformed by oncogenic ras or trigger senescence in normal cells. Conversely, the anti-senescence viral oncoproteins E1A, E6, and E7 prevented SAPD. In human prostate neoplasms, high levels of phosphorylated ERK were found in benign lesions, correlating with other senescence markers and low levels of STAT3, one of the SAPD targets. We thus identified a mechanism that links aberrant activation of growth signaling pathways and short telomeres to protein degradation and cellular senescence.
authors.affiliation: Département de Biochimie, Université de Montréal, Montréal, Québec H3C 3J7, Canada.
authors.forename: Xavier
authors.initials: X
authors.lastname: Deschênes-Simard
authors.forename: Marie-France
authors.initials: MF
authors.lastname: Gaumont-Leclerc
authors.forename: Véronique
authors.initials: V
authors.lastname: Bourdeau
authors.forename: Frédéric
authors.initials: F
authors.lastname: Lessard
authors.forename: Olga
authors.initials: O
authors.lastname: Moiseeva
authors.forename: Valérie
authors.initials: V
authors.lastname: Forest
authors.forename: Sebastian
authors.initials: S
authors.lastname: Igelmann
authors.forename: Frédérick A
authors.initials: FA
authors.lastname: Mallette
authors.forename: Marc K
authors.initials: MK
authors.lastname: Saba-El-Leil
authors.forename: Sylvain
authors.initials: S
authors.lastname: Meloche
authors.forename: Fred
authors.initials: F
authors.lastname: Saad
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Mes-Masson
authors.forename: Gerardo
authors.initials: G
authors.lastname: Ferbeyre
mesh_terms: D000818:Animals; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D016922:Cellular Senescence / Q000235:genetics*; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000201:enzymology; D055785:Gene Knockdown Techniques; D006801:Humans; D020935:MAP Kinase Signaling System / Q000235:genetics / Q000502:physiology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D059748:Proteolysis; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism
chemical_list: D025521:Tumor Suppressor Proteins; D046988:Proteasome Endopeptidase Complex; D018631:ras Proteins