Werner syndrome protein limits MYC-induced cellular senescence

  1. Carla Grandori1,11,
  2. Kou-Juey Wu2,7,
  3. Paula Fernandez3,9,
  4. Celine Ngouenet1,
  5. Jonathan Grim1,
  6. Bruce E. Clurman1,
  7. Michael J. Moser4,8,
  8. Junko Oshima4,
  9. David W. Russell5,
  10. Karen Swisshelm4,
  11. Scott Frank3,
  12. Bruno Amati3,10,
  13. Riccardo Dalla-Favera2, and
  14. Raymond J. Monnat, Jr.4,6
  1. 1Basic Sciences, Human Biology and Clinical Divisions, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA
  2. 2Institute for Cancer Genetics and the Department of Pathology, Columbia University, New York, New York 10032, USA
  3. 3Department of Oncology, DNAX Research Institute, Palo Alto, California 94304, USA
  4. 4Department Pathology, University of Washington, Seattle, Washington 98195, USA
  5. 5Department of Medicine, University of Washington, Seattle, Washington 98195, USA
  6. 6Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA

Abstract

The MYC oncoprotein is a transcription factor that coordinates cell growth and division. MYC overexpression exacerbates genomic instability and sensitizes cells to apoptotic stimuli. Here we demonstrate that MYC directly stimulates transcription of the human Werner syndrome gene, WRN, which encodes a conserved RecQ helicase. Loss-of-function mutations in WRN lead to genomic instability, an elevated cancer risk, and premature cellular senescence. The overexpression of MYC in WRN syndrome fibroblasts or after WRN depletion from control fibroblasts led to rapid cellular senescence that could not be suppressed by hTERT expression. We propose that WRN up-regulation by MYC may promote MYC-driven tumorigenesis by preventing cellular senescence.

Keywords

Footnotes

  • Supplemental material is available at http://parma.fhcrc.org/CGrandori.

  • Article and publication are at http://www.genesdev.org/cgi/doi/10.1101/gad.1100303.

  • ↵7 Present address: Department of Genomic Medicine, National Taiwan University Hospital, Taipei 100, Taiwan.

  • ↵8 Present address: EraGen Biosciences, Madison, WI 53717, USA.

  • ↵9 Present address: University of Bern, Langgass-Strasse 122, CH-3001 Bern, Switzerland.

  • ↵10 Present address: Department of Experimental Oncology, European Institute of Oncology, 20141 Milan, Italy.

  • Corresponding author.

  • ↵11 E-MAIL cgrandor{at}fhcrc.org; FAX (206) 667-6522.

    • Accepted May 2, 2003.
    • Received April 3, 2003.
| Table of Contents

This Article

  1. doi: 10.1101/gad.1100303 Genes & Dev. 17: 1569-1574 Cold Spring Harbor Laboratory Press

Article Category

Share

Current Issue

  1. March 1, 2024, 38 (5-6)
  1. Current Issue
  1. Alert me to new issues of G&D

Life Science Alliance