The E3 SUMO ligase PIASy is a regulator of cellular senescence and apoptosis

Oliver Bischof; Klaus Schwamborn; Nadine Martin; Andreas Werner; Claudio Sustmann; Rudolf Grosschedl; Anne Dejean

doi:10.1016/j.molcel.2006.05.016

The E3 SUMO ligase PIASy is a regulator of cellular senescence and apoptosis

Mol Cell. 2006 Jun 23;22(6):783-794. doi: 10.1016/j.molcel.2006.05.016.

Authors

Oliver Bischof¹, Klaus Schwamborn¹, Nadine Martin¹, Andreas Werner¹, Claudio Sustmann², Rudolf Grosschedl², Anne Dejean³

Affiliations

¹ Nuclear Organisation and Oncogenesis Unit, INSERM U579, Institut Pasteur, 75724 Paris Cedex 15, France.
² Max-Planck-Institute of Immunobiology, D-79108 Freiburg, Germany.
³ Nuclear Organisation and Oncogenesis Unit, INSERM U579, Institut Pasteur, 75724 Paris Cedex 15, France. Electronic address: adejean@pasteur.fr.

PMID: 16793547
DOI: 10.1016/j.molcel.2006.05.016

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.

Publication types

Research Support, Non-U.S. Gov't
Retracted Publication

MeSH terms

Apoptosis / physiology*
Cell Transformation, Viral / genetics
Cellular Senescence / physiology*
E2F Transcription Factors / genetics
E2F Transcription Factors / metabolism
Fibroblasts / cytology
Fibroblasts / physiology*
Gene Expression / genetics
Humans
Oncogene Proteins, Viral / genetics
Oncogene Proteins, Viral / metabolism
Poly-ADP-Ribose Binding Proteins
Protein Inhibitors of Activated STAT / deficiency
Protein Inhibitors of Activated STAT / metabolism*
Protein Processing, Post-Translational
Response Elements / genetics
Retinoblastoma Protein / genetics
Retinoblastoma Protein / metabolism*
SUMO-1 Protein / genetics
SUMO-1 Protein / metabolism
Transfection
Tumor Suppressor Protein p53 / genetics
Tumor Suppressor Protein p53 / metabolism
Ubiquitin-Protein Ligases / genetics
Ubiquitin-Protein Ligases / metabolism

Substances

E2F Transcription Factors
E6 protein, Human papillomavirus type 11
Oncogene Proteins, Viral
PIAS4 protein, human
Poly-ADP-Ribose Binding Proteins
Protein Inhibitors of Activated STAT
Retinoblastoma Protein
SUMO-1 Protein
Tumor Suppressor Protein p53
Ubiquitin-Protein Ligases