Loss of p27(Kip1) accelerates DNA replication after partial hepatectomy in mice.
BACKGROUND
Liver regeneration after partial hepatectomy (PH) is accomplished by a synchronous replication of hepatocytes. Both positive and negative regulators of cyclin-dependent protein kinase (Cdk) have been implicated in hepatocyte proliferation, but their specific roles in vivo remain to be clarified. To investigate the specific role of p27(Kip1), a member of the Cip/Kip family of Cdk inhibitors, in cell-cycle regulation during liver regeneration, p27-knockout mice were studied after PH.


METHODS
Under ether anesthesia, mice were subjected to 70% PH. Animals were sacrificed at intervals after the surgery, and the remnant liver was harvested and analyzed.


RESULTS
In p27-deficient mice, the timing of DNA synthesis was significantly accelerated with a perturbation in the ordered distribution of proliferating cells in the hepatic lobule. p27 deficiency, however, did not affect the whole population of cycling cells, the number of apoptotic cells, or liver injury and mortality after PH.


CONCLUSIONS
These data provide in vivo evidence that p27 functions as a brake in the "start" of the hepatocyte cell cycle, thereby coordinating temporally and spatially the onset of DNA synthesis of hepatocytes within the hepatic lobules.
Hayashi
Eiji
E
Department of Geriatric Research, National Institute for Longevity Sciences, Obu, Aichi, Japan.
Yasui
Akihiro
A
Oda
Koji
K
Nagino
Masato
M
Nimura
Yuji
Y
Nakanishi
Makoto
M
Motoyama
Noboru
N
Ikeda
Kyoji
K
Matsuura
Akira
A
D000818:Animals; D017209:Apoptosis; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000502:physiology; D002455:Cell Division; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004247:DNA / Q000096:biosynthesis; D004261:DNA Replication; D006498:Hepatectomy / Q000401:mortality; D020287:In Situ Nick-End Labeling; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008938:Mitosis; D025521:Tumor Suppressor Proteins / Q000172:deficiency* / Q000502:physiology
C493961:Cdkn1b protein, mouse; D018797:Cell Cycle Proteins; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004247:DNA