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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.
| Content Provider | Semantic Scholar |
|---|---|
| Author | Dasari, Arvind Bartholomew, Janine N. Volonté, Daniela Galbiati, Ferruccio |
| Copyright Year | 2006 |
| Abstract | Cellular senescence is believed to represent a natural tumor suppressor mechanism. We have previously shown that up-regulation of caveolin-1 was required for oxidative stress-induced 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 (-1,296) 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 -244/-222 and -124/-101. The hydrogen peroxide-mediated activation of both Cav-1 (-244/-222) and Cav-1 (-124/-101) 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 -238/-231 and -118/-106 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. |
| File Format | PDF HTM / HTML |
| DOI | 10.1158/0008-5472.CAN-06-1236 |
| PubMed reference number | 17108117 |
| Journal | Medline |
| Volume Number | 66 |
| Issue Number | 22 |
| Alternate Webpage(s) | http://diyhpl.us/~bryan/papers2/longevity/Oxidative%20Stress%20Induces%20Premature%20Senescence%20by%20Stimulating%20Caveolin-1%20Gene%20Transcription%20through%20p38%20Mitogen-Activated%20Protein%20Kinase-Sp1%EF%BF%BD%EF%BF%BD%EF%BF%BDMediated%20Activation%20of%20Two%20GC-Rich%20Promoter%20Elements.pdf |
| Alternate Webpage(s) | https://doi.org/10.1158/0008-5472.CAN-06-1236 |
| Journal | Cancer research |
| Language | English |
| Access Restriction | Open |
| Content Type | Text |
| Resource Type | Article |
