Recovery of mitogenic signaling by reduction of caveolin-1 in senescent cells
Kyung A Cho, Sung Jin Ryu, Kyung Tae Kim, Ik Soon Jang and Sang Chul Park*
The Aging and Apoptosis Research Center, Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul, 110-799, 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 (HDF). 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 could sucessfully reduce the level of caveolin-1 in
senescent HDFs using its antisense-oligonucleotides and small
interfering RNA (siRNA), 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 EGF stimulation. Moreover, DNA synthesis and the re-entry of
senescent cells into cell cycle were resumed upon EGF stimulation
concomitantly with decreases in p53 and p21. Moreover, by adjusting
caveolin status in senescent cells, morphological shape can be regained
like young cells. These morphological changes of senescent cells were
induced by disruption of focal adhesion complexes and caveolin-1 in
membrane.
Taken together, we conclude that the senescent phenotype including the
loss of mitogenic signaling and morphological changes is strongly
related to their elevated levels of caveolin-1. In consequence, it can
be anticipated that a new field of study is about to open, aimed at
developing strategies to overcome the senescence-related functional
deterioration and morphological alterations.
Key words:
senescent, caveolin-1, mitogenic signaling, morphology, focal adhesion
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