Up-regulation of caveolin attenuates epidermal growth factor signaling in senescent cells.
Senescent human diploid fibroblasts do not respond to growth factors like epidermal growth factor (EGF), although they have a normal level of receptors and downstream signaling molecules. To examine the mechanism of signaling attenuation, we investigated Erk activation after EGF stimulation in senescent cells. Senescent cells did not phosphorylate Erk-1/2 after EGF stimulation, whereas young cells did. In those senescent cells, we found an increased level of caveolin proteins and strong interactions between caveolin-1 and EGF receptor. Electron microscopic analysis demonstrated an increased number of caveolae structures in senescent cells. More interestingly, brain, spleen, and lung from 26-month-old rats showed substantial increases of caveolin proteins. However, in the case of p53-induced senescence, caveolin-1 was not induced, and EGF stimulation phosphorylated Erk-1/2 as much as young control cells. Finally, we overexpressed caveolin-1 in young human diploid fibroblasts in which the activation of Erk-1/2 upon EGF stimulation was significantly suppressed. These results suggest that the unresponsiveness of senescent fibroblasts to EGF stimulation may be due to the overexpression of caveolins, which seems to be independent of growth arrest and other aging phenotypes.
Park
W Y
WY
Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul 110-799, Korea.
Park
J S
JS
Cho
K A
KA
Kim
D I
DI
Ko
Y G
YG
Seo
J S
JS
Park
S C
SC
D000818:Animals; D051242:Caveolin 1; D022461:Caveolins; D016922:Cellular Senescence; D004789:Enzyme Activation; D004815:Epidermal Growth Factor / Q000378:metabolism*; D005260:Female; D005347:Fibroblasts; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D008854:Microscopy, Electron; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D015854:Up-Regulation
C495540:CAV1 protein, human; C495537:Cav1 protein, rat; D051242:Caveolin 1; D022461:Caveolins; D008565:Membrane Proteins; D004815:Epidermal Growth Factor; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases