Senescent phenotype can be reversed by reduction of caveolin status.
Hyporesponsiveness to growth factors is one of the fundamental characteristics of senescent cells. We previously reported that the up-regulation of caveolin attenuates the growth factor response and the subsequent downstream signal cascades in senescent human diploid fibroblasts. Therefore, in the present experiment, we investigated the modulation of caveolin status in senescent cells to determine the effect of caveolin on mitogenic signaling efficiency and cell cycling. We reduced the level of caveolin-1 in senescent human diploid fibroblasts using its antisense oligonucleotides and small interfering RNA, and this resulted in the restoration of normal growth factor responses such as the increased phosphorylation of Erk, the nuclear translocation of p-Erk, and the subsequent activation of p-Elk upon epidermal growth factor stimulation. Moreover, DNA synthesis and the re-entry of senescent cells into cell cycle were resumed upon epidermal growth factor stimulation concomitantly with decreases in p53 and p21. Taken together, we conclude that the loss of mitogenic signaling in senescent cells is strongly related to their elevated levels of caveolin-1 and that the functional recovery of senescent cells at least in the terms of growth factor responsiveness and cell cycle entry might be achieved simply by lowering the caveolin level.
The Aging and Apoptosis Research Center, Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul 110-799, Korea.
Kyung A
KA
Cho
Sung Jin
SJ
Ryu
Jeong Soo
JS
Park
Ik Soon
IS
Jang
Jeong Soo
JS
Ahn
Kyung Tae
KT
Kim
Sang Chul
SC
Park
D015153:Blotting, Western; D051242:Caveolin 1; D022461:Caveolins / Q000378:metabolism*; D002453:Cell Cycle; D002455:Cell Division; D002478:Cells, Cultured; D016922:Cellular Senescence; D004247:DNA / Q000096:biosynthesis / Q000378:metabolism; D015536:Down-Regulation; D004815:Epidermal Growth Factor / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008854:Microscopy, Electron; D008856:Microscopy, Fluorescence; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000378:metabolism; D010641:Phenotype; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction; D013347:Subcellular Fractions / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D015854:Up-Regulation
C495540:CAV1 protein, human; D051242:Caveolin 1; D022461:Caveolins; D016376:Oligonucleotides, Antisense; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; D004815:Epidermal Growth Factor; D004247:DNA; D020928:Mitogen-Activated Protein Kinases; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)