Inhibition of nuclear factor-erythroid 2-related factor (Nrf2) by caveolin-1 promotes stress-induced premature senescence

Daniela Volonte, Zhongmin Liu, Paul M. Musille, Elena Stoppani, Nobunao Wakabayashi, Yuan Pu Di, Michael P. Lisanti, Thomas W. Kensler, Ferruccio Galbiati

Research output: Contribution to journalArticle

Abstract

Reactive oxygen species (ROS) can induce premature cellular senescence, which is believed to contribute to aging and age-related diseases. The nuclear erythroid 2 p45-related factor-2 (Nrf2) is a transcription factor that mediates cytoprotective responses against stress. We demonstrate that caveolin-1 is a direct binding partner of Nrf2, as shown by the binding of the scaffolding domain of caveolin-1 (amino acids 82-101) to the caveolin-binding domain of Nrf2 (amino acids 281-289). Biochemical studies show that Nrf2 is concentrated into caveolar membranes in human and mouse fibroblasts, where it colocalizes with caveolin- 1, under resting conditions. After oxidative stress, caveolin-1 limits the movement of Nrf2 from caveolar membranes to the nucleus. In contrast, Nrf2 is constitutively localized to the nucleus before and after oxidative stress in caveolin-1-null mouse embryonic fibroblasts (MEFs), which do not express caveolin-1. Functional studies demonstrate that caveolin-1 acts as an endogenous inhibitor of Nrf2, as shown by the enhanced up-regulation of NQO1, an Nrf2 target gene, in caveolin-1-null MEFs and the activation or inhibition of a luciferase construct carrying an antioxidant responsive element (ARE) after down-regulation of caveolin-1 by small interfering RNA or overexpression of caveolin-1, respectively. Expression of a mutant form of Nrf2 that cannot bind to caveolin-1 (F?A-Nrf2) hyperactivates ARE and inhibits oxidative stress-induced activation of the p53/p21Waf1/Cip1 pathway and induction of premature senescence in fibroblasts. Finally, we show that overexpression of caveolin-1 in colon cancer cells inhibits oxidant-induced activation of Nrf2-dependent signaling, promotes premature senescence, and inhibits their transformed phenotype. Thus, by inhibiting Nrf2-mediated signaling, caveolin-1 links free radicals to the activation of the p53/senescence pathway.

Original languageEnglish (US)
Pages (from-to)1852-1862
Number of pages11
JournalMolecular biology of the cell
Volume24
Issue number12
DOIs
StatePublished - Jun 15 2013
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    Volonte, D., Liu, Z., Musille, P. M., Stoppani, E., Wakabayashi, N., Di, Y. P., Lisanti, M. P., Kensler, T. W., & Galbiati, F. (2013). Inhibition of nuclear factor-erythroid 2-related factor (Nrf2) by caveolin-1 promotes stress-induced premature senescence. Molecular biology of the cell, 24(12), 1852-1862. https://doi.org/10.1091/mbc.E12-09-0666