title: The E3 SUMO ligase PIASy is a regulator of cellular senescence and apoptosis.
abstract: Cellular senescence and apoptosis have evolved to restrain unwarranted proliferation of potentially tumorigenic cells. Here we show that overexpression of the E3 SUMO ligase PIASy in normal human fibroblasts recruits the p53 and Rb tumor suppressor pathways to provoke a senescence arrest. By contrast, in Rb-deficient fibroblasts, expression of PIASy leads to p53-dependent apoptosis. Induction of senescence requires PIASy E3 activity and is specific for this member of the PIAS ligase family. PIASy stimulates sumoylation and transcriptional activity of p53 and increases Rb-dependent corepression through recruitment to E2F-responsive promoters. Viral oncoprotein E6 suppresses both PIASy-induced senescence and sumoylation of PIASy substrates. Finally, we show that fibroblasts lacking PIASy exhibit a highly reduced propensity to undergo senescence in response to a prosenescence stimulus. Altogether, these data provide the first evidence for a direct role of an E3 SUMO ligase, and by implication of the SUMO pathway, in cellular senescence and apoptosis.
authors.affiliation: Nuclear Organisation and Oncogenesis Unit, INSERM U579, Institut Pasteur, 75724 Paris Cedex 15, France.
authors.forename: Oliver
authors.initials: O
authors.lastname: Bischof
authors.affiliation: Nuclear Organisation and Oncogenesis Unit, INSERM U579, Institut Pasteur, 75724 Paris Cedex 15, France.
authors.forename: Klaus
authors.initials: K
authors.lastname: Schwamborn
authors.affiliation: Nuclear Organisation and Oncogenesis Unit, INSERM U579, Institut Pasteur, 75724 Paris Cedex 15, France.
authors.forename: Nadine
authors.initials: N
authors.lastname: Martin
authors.affiliation: Nuclear Organisation and Oncogenesis Unit, INSERM U579, Institut Pasteur, 75724 Paris Cedex 15, France.
authors.forename: Andreas
authors.initials: A
authors.lastname: Werner
authors.affiliation: Max-Planck-Institute of Immunobiology, D-79108 Freiburg, Germany.
authors.forename: Claudio
authors.initials: C
authors.lastname: Sustmann
authors.affiliation: Max-Planck-Institute of Immunobiology, D-79108 Freiburg, Germany.
authors.forename: Rudolf
authors.initials: R
authors.lastname: Grosschedl
authors.affiliation: Nuclear Organisation and Oncogenesis Unit, INSERM U579, Institut Pasteur, 75724 Paris Cedex 15, France. Electronic address: adejean@pasteur.fr.
authors.forename: Anne
authors.initials: A
authors.lastname: Dejean
mesh_terms: D017209:Apoptosis / Q000502:physiology*; D002472:Cell Transformation, Viral / Q000235:genetics; D016922:Cellular Senescence / Q000502:physiology*; D050684:E2F Transcription Factors / Q000235:genetics / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology*; D015870:Gene Expression / Q000235:genetics; D006801:Humans; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000378:metabolism; D000075223:Poly-ADP-Ribose Binding Proteins; D050828:Protein Inhibitors of Activated STAT / Q000172:deficiency / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D020218:Response Elements / Q000235:genetics; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism*; D025842:SUMO-1 Protein / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism
chemical_list: D050684:E2F Transcription Factors; C469553:E6 protein, Human papillomavirus type 11; D009856:Oncogene Proteins, Viral; C485891:PIAS4 protein, human; D000075223:Poly-ADP-Ribose Binding Proteins; D050828:Protein Inhibitors of Activated STAT; D016160:Retinoblastoma Protein; D025842:SUMO-1 Protein; D016159:Tumor Suppressor Protein p53; D044767:Ubiquitin-Protein Ligases