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A potential mechanism for short time exposure to hypoxia-induced DNA synthesis in primary cultured chicken hepatocytes: Correlation between Ca2+/PKC/MAPKs and PI3K/Akt/mTOR

Cited 13 time in Web of Science Cited 13 time in Scopus
Authors
Lee, Sang Hun; Lee, Min Young; Lee, Jang-Hern; Han, Ho Jae
Issue Date
2008-07-21
Publisher
Wiley-Blackwell
Citation
J Cell Biochem 104(5):1598-1611
Keywords
hepatocytesPI3K/AktmTORPKCMAPK
Abstract
Less information is available concerning the molecular mechanisms of cell survival after hypoxia in
hepatocytes. Therefore, this study examined the effect of hypoxia on DNA synthesis and its related signal cascades in
primary cultured chicken hepatocytes. Hypoxia increased [3H] thymidine incorporation, which was increased
significantly after 0–24 h of hypoxic exposure. Indeed, the percentage of cell population in the S phase was increased
in hypoxia condition. However, the release of LDH indicating cellular injury was not changed under hypoxic conditions.
Hypoxia increased Ca2þ uptake and PKC translocation from the cytosol to the membrane fraction. Among the PKC
isoforms, hypoxia stimulated the translocation of PKC a and e. Hypoxia also phosphorylated the p38 and p44/42 mitogenactivated
protein kinases (MAPKs), which were blocked by the inhibition of PKC. On the other hand, hypoxia increased
Akt and mTOR phosphorylation, which was blocked in the absence of intra/extracellular Ca2þ. The inhibition of
PKC/MAPKs or PI3K/Akt pathway blocked the hypoxia-induced [3H] thymidine incorporation. However, hypoxiainduced
Ca2þ uptake and PKC translocation was not influenced by LY 294002 or Akt inhibitor and hypoxia-induced
MAPKs phosphorylation was not changed by rapamycin. In addition, LY 294002 or Akt inhibitor has no effect on the
phosphorylation of MAPKs. It suggests that there is no direct interaction between the two pathways, which cooperatively
mediated cell cycle progression to hypoxia in chicken hepatocytes. Hypoxia also increased the level of the cell cycle
regulatory proteins [cyclin D1, cyclin E, cyclin-dependent kinase (CDK) 2, and CDK 4] and p-RB protein but decreased
the p21 and p27 expression levels, which were blocked by inhibitors of upstream signal molecules. In conclusion,
short time exposure to hypoxia increases DNA synthesis in primary cultured chicken hepatocytes through cooperation
of Ca2þ/PKC, p38 MAPK, p44/42 MAPKs, and PI3K/Akt pathways.
ISSN
0730-2312
Language
English
URI
https://hdl.handle.net/10371/8287
DOI
https://doi.org/10.1002/jcb.21657
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College of Veterinary Medicine (수의과대학)Dept. of Veterinary Medicine (수의학과)Journal Papers (저널논문_수의학과)
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