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Attenuation of EGF signaling in senescent cells by caveolin
1Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Korea.
Abstract:
One of the characteristics of senescent cells is unresponsiveness to external stimuli like EGF. Although they have a normal level of receptors and downstream signaling molecules, EGF cannot induce the activation of Erk kinases and DNA synthesis in senescent cells as much as in young cells. Caveolin proteins directly interact with signaling molecules including EGF receptor and suppress the activation of EGFR upon EGF stimulation. We found that Erk activation after EGF stimulation in senescent human diploid fibroblasts was down-regulated. Those senescent cells showed an increased level of three isoforms of caveolin proteins. This change seems to lie in transcriptional control in senescent cells. We also demonstrated up-regulated caveolin proteins were co-localized with EGFR proteins in detergent-insoluble fractions. From these results, we suggest that the up-regulated expression of caveolin might explain the unresponsiveness of senescent fibroblasts to EGF stimulation.
Insights
Senescent cells resist epidermal growth factor (EGF) stimulation due to increased caveolin proteins. These proteins interact with the EGF receptor, hindering Erk kinase activation and DNA synthesis in aging cells.
Area of Science:
- Cellular senescence
- Molecular biology
- Biochemistry
Background:
- Senescent cells exhibit unresponsiveness to external stimuli like EGF.
- Despite normal receptor levels, EGF fails to fully activate Erk kinases and DNA synthesis in senescent cells.
- Caveolin proteins are known to interact with signaling molecules, including the EGF receptor, potentially suppressing its activation.
Purpose of the Study:
- To investigate the role of caveolin proteins in the EGF unresponsiveness of senescent human diploid fibroblasts.
- To determine if altered caveolin expression correlates with reduced Erk activation upon EGF stimulation.
Main Methods:
- Assessed Erk kinase activation and DNA synthesis in response to EGF stimulation in senescent and young fibroblasts.
- Quantified the expression levels of caveolin protein isoforms in senescent cells.
- Investigated the localization of caveolin and EGF receptor proteins within cellular fractions.
Main Results:
- EGF stimulation resulted in down-regulated Erk activation in senescent human diploid fibroblasts compared to young cells.
- Senescent cells displayed increased levels of three caveolin protein isoforms, suggesting transcriptional regulation.
- Up-regulated caveolin proteins were found to co-localize with EGF receptor proteins in detergent-insoluble cellular fractions.
Conclusions:
- Increased expression of caveolin proteins in senescent fibroblasts contributes to their unresponsiveness to EGF stimulation.
- Caveolin's interaction with the EGF receptor in specific cellular compartments may underlie this phenomenon.
- This finding provides insight into the molecular mechanisms governing cellular senescence and signal transduction.