Plasminogen activator inhibitor 1 - Insulin-like growth factor binding protein 3 cascade regulates stress-induced senescence

David J. Elzi, Yanlai Lai, Meihua Song, Kevin Hakala, Susan T. Weintraub, Yuzuru Shiio

Research output: Contribution to journalArticlepeer-review

68 Scopus citations

Abstract

Cellular senescence is widely believed to play a key role in tumor suppression, but the molecular pathways that regulate senescence are only incompletely understood. By using a secretome proteomics approach, we identified insulin-like growth factor binding protein 3 (IGFBP3) as a secreted mediator of breast cancer senescence upon chemotherapeutic drug treatment. The senescenceinducing activity of IGFBP3 is inhibited by tissue-type plasminogen activator-mediated proteolysis, which is counteracted by plasminogen activator inhibitor 1 (PAI-1), another secreted mediator of senescence. We demonstrate that IGFBP3 is a critical downstream target of PAI-1-induced senescence. These results suggest a role for an extracellular cascade of secreted proteins in the regulation of cellular senescence.

Original languageEnglish (US)
Pages (from-to)12052-12057
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number30
DOIs
StatePublished - Jul 24 2012

Keywords

  • Chemotherapy
  • Isotope-coded affinity tag
  • Protease
  • Protease inhibitor
  • Protein secretion

ASJC Scopus subject areas

  • General

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