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J. Biol. Chem., Vol. 278, Issue 30, 27789-27795, July 25, 2003

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Senescent Phenotype Can Be Reversed by Reduction of Caveolin Status^*

Kyung A. Cho , Sung Jin Ryu , Jeong Soo Park , Ik Soon Jang , Jeong Soo Ahn , Kyung Tae Kim  and Sang Chul Park  ¶

From the The Aging and Apoptosis Research Center, Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul 110-799, Korea and Department of Biochemistry, College of Medicine, Dankook University, Cheonan, Korea

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.

Received for publication, August 8, 2002 , and in revised form, April 17, 2003.

^* This work has been supported by the grants from the Aging and Apoptosis Research Center (RII-2002-001-01-001), the Korea Research Foundation for Health Science, and the Virtual Research Institute of Aging, Nippon Boehringer Ingelheim. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed. Tel.: 82-2-740-8244; Fax: 82-2-744-4534; E-mail: scpark{at}snu.ac.kr.

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