Oxidative Stress Induces Premature Senescence by Stimulating Caveolin-1 Gene Transcription through p38 Mitogen-Activated Protein Kinase/Sp1–Mediated Activation of Two GC-Rich Promoter Elements

Abstract

Cellular senescence is believed to represent a natural tumor suppressor mechanism. We have previously shown that upregulation of caveolin-1 was required for oxidative stressinduced premature senescence in fibroblasts. However, the molecular mechanisms underlying caveolin-1 up-regulation in senescent cells remain unknown. Here, we show that subcytotoxic oxidative stress generated by hydrogen peroxide application promotes premature senescence and stimulates the activity of a (À1,296) caveolin-1 promoter reporter gene construct in fibroblasts. Functional deletion analysis mapped the oxidative stress response elements of the mouse caveolin-1 promoter to the sequences À244/À222 and À124/À101. The hydrogen peroxide-mediated activation of both Cav-1 (À244/ À222) and Cav-1 (À124/À101) was prevented by the antioxidant quercetin. Combination of electrophoretic mobility shift studies, chromatin immunoprecipitation analysis, Sp1 overexpression experiments, as well as promoter mutagenesis identifies enhanced Sp1 binding to two GC-boxes at À238/ À231 and À118/À106 as the core mechanism of oxidative stress-triggered caveolin-1 transactivation. In addition, signaling studies show p38 mitogen-activated protein kinase (MAPK) as the upstream regulator of Sp1-mediated activation of the caveolin-1 promoter following oxidative stress. Inhibition of p38 MAPK prevents the oxidant-induced Sp1-mediated up-regulation of caveolin-1 protein expression and development of premature senescence. Finally, we show that oxidative stress induces p38-mediated up-regulation of caveolin-1 and premature senescence in normal human mammary epithelial cells but not in MCF-7 breast cancer cells, which do not express caveolin-1 and undergo apoptosis. This study delineates for the first time the molecular mechanisms that modulate caveolin-1 gene transcription upon oxidative stress and brings new insights into the redox control of cellular senescence in both normal and cancer cells.

Disruption of xCT inhibits cancer cell metastasis via the caveolin-1/β-catenin pathway

“…Thus, xCT is essential for maintaining the homeostasis of intracellular ROS. Recently, p38 MAPK has been suggested to be involved in the transcriptional upregulation of caveolin-1 stimulated by oxidative stress (Volonte et al, 2002;Dasari et al, 2006). We hypothesized that xCT disruption may lead to excessive accumulation of ROS and triggers oxidative stress, which activates p38 MAPK xCT in cancer metastasis R-S Chen et al and thus transactivates caveolin-1 expression and inhibits cancer cell invasion.…”

Tissue damage negatively regulates LPS-induced macrophage necroptosis

“…Previous studies have reported that transcription factor Sp1 regulates caveolin-1 gene expression. 39 We thus hypothesized that RAGE signaling acting through Sp1 upregulates caveolin-1 expression, which then promotes caveolae-mediated TLR4 internalization.…”

Inonotus obliquus Protects against Oxidative Stress-Induced Apoptosis and Premature Senescence

“…Oxidative stress has been shown to induce stress-induced premature senescence in fibroblasts (Dasari et al, 2006;Frippiat et al, 2001). Senescent cells show different features from proliferative cells.…”

“…Oxidative stress has been shown to induce stress-induced premature senescence in fibroblasts (Dasari et al, 2006;Frippiat et al, 2001). Stress-induced premature senescence was recently invoked as an explanation of irreversible growth arrest characterized by senescence-specific cell morphology and gene expression, similar to the phenomenon of replicative senescence (Touissant et al, 2000).…”