血小板衍生生長因子促進腎膈細胞細胞週期的訊息傳導機轉
Other Title
Pentoxifylline Inhibits Platelet-Derived Growth Factor-Stimulated
Cyclin D1 Expression in Mesangial Cells by
Blocking Akt Membrane Translocation
Cyclin D1 Expression in Mesangial Cells by
Blocking Akt Membrane Translocation
Resource
MOLECULAR PHARMACOLOGY 64(4),811-822
Journal
MOLECULAR PHARMACOLOGY 64
Pages
811-822
Date Issued
2003
Date
2003
Author(s)
林水龍
DOI
912314B002347
Abstract
Pentoxifylline (PTX) is a potent inhibitor of mesangial cell pro-liferation,
but its underlying mechanism is poorly understood.
Here, we demonstrate that in platelet-derived growth factor
(PDGF)-stimulated mesangial cells, PTX causes G1 arrest by
down-regulation of cyclin D1 expression, which subsequently
attenuates Cdk4 activity. In vivo, PTX similarly reduces cyclin
D1 expression in mesangial cells of rats with acute Thy1 glo-merulonephritis.
The mechanism by which PTX reduces cyclin
D1 is also investigated. PTX blocks Akt but not phosphatidyl-inositol
3-kinase (PI3K) activation in response to PDGF and
abrogates cyclin D1 induction by PI3K, suggesting an effect of
PTX on Akt itself. Indeed, PTX is capable of blocking the
membrane translocation of Akt, and enforced targeting of Akt
to cell membrane prevents the inhibition of Akt and cyclin D1 by
PTX. Because PTX is known to increase intracellular cAMP
levels by inhibiting phosphodiesterase, the role of protein ki-nase
A (PKA) in these events is investigated. The PKA antago-nist
N-[2-(4-bromocinnamylamino)ethyl]-5-isoquinoline (H89)
abolishes cell proliferation effects of PTX and restores cyclin D1
expression as well as Akt membrane translocation and activa-tion
by PDGF, whereas dibutyryl cAMP and forskolin recapitu-late
the functions of PTX in mesangial cells. In conclusion, our
results indicate that PTX, acting through PKA, interferes with
PDGF signaling to Akt activation by blocking Akt membrane
translocation, thereby inhibiting cyclin D1 expression and mes-angial
cell proliferation.
Publisher
臺北市：國立臺灣大學醫學院內科
Type
report
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