title: E6AP is required for replicative and oncogene-induced senescence in mouse embryo fibroblasts.
abstract: Cellular senescence is important for the maintenance of tissue homeostasis, and has recently been shown to pose a natural barrier to tumorigenesis. The E3 ubiquitin ligase, E6AP, has been linked to a number of protein regulators of the cell cycle as well as the cellular stress response. We therefore explored the role of E6AP in the cellular response to stress. We found that mouse embryo fibroblasts (MEFs) lacking E6AP escape replicative senescence, as well as Ras-induced senescence associated with impaired markers. E6AP-deficient MEFs exhibit a range of transformed phenotypes: these include the ability to grow under stress conditions (such as low serum and DNA damage), enhanced proliferation, anchorage independent growth and enhanced growth of xenografts in mice. The transformed phenotype of E6AP-deficient MEFs is associated with lower basal and stress-induced accumulation of p53. Overall, our study implicates E6AP as an important regulator of the cellular response to stress, in particular through the regulation of replicative and oncogene-induced senescence.
authors.affiliation: Lautenberg Center for General and Tumor Immunology, The Hebrew University Hadassah Medical School, Jerusalem, Israel.
authors.forename: Y
authors.initials: Y
authors.lastname: Levav-Cohen
authors.forename: K
authors.initials: K
authors.lastname: Wolyniec
authors.forename: O
authors.initials: O
authors.lastname: Alsheich-Bartok
authors.forename: A-L
authors.initials: AL
authors.lastname: Chan
authors.forename: S J
authors.initials: SJ
authors.lastname: Woods
authors.forename: Y-H
authors.initials: YH
authors.lastname: Jiang
authors.forename: S
authors.initials: S
authors.lastname: Haupt
authors.forename: Y
authors.initials: Y
authors.lastname: Haupt
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D016922:Cellular Senescence; D004622:Embryo, Mammalian / Q000166:cytology; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism* / Q000528:radiation effects; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D013312:Stress, Physiological; D014183:Transplantation, Heterologous; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000502:physiology*
chemical_list: D016159:Tumor Suppressor Protein p53; C502429:Ube3a protein, mouse; D044767:Ubiquitin-Protein Ligases