Disruption of Phospholipase Cδ4 Gene Modulates the Liver Regeneration in Cooperation with Nuclear Protein Kinase C

Abstract

Phospholipase Cδ4 (PLC δ4) gene has been cloned from the cDNA library of regenerating rat liver. Using PLC δ4 gene–disrupted mice (PLC δ4^−/−), we studied a role of PLC δ4 during liver regeneration after partial hepatectomy (PH). In PLC δ4^−/−, liver regeneration occurred in an apparently normal way. However, BrdU-indices indicated that PLC δ4 gene disruption delayed the onset of DNA synthesis by 2 h. Noticeably, the BrdU-indices in PLC δ4^+/+ remained rather constant throughout S phase, 25–35%, whereas in PLC δ4^−/−, it fluctuated drastically from 25% at 34 h to 65% at late S, 42 h after PH. This fact showed that PLC δ4 gene disruption caused a higher synchronization of cell proliferation. The mRNA for PLC δ4 in PLC δ4^+/+ appeared at late G1, and the expression continued throughout S phase. PLC activity increased transiently in chromatin at the late G1 and S phases in only PLC δ4^+/+, but not in PLC δ4^−/−. The specific increases in PLC activity well correlated with the transient increases of protein kinase C (PKC) α in chromatin of PLC δ4^+/+. PKC ε also increased transiently in chromatin from PLC δ4^+/+ at late S. It is concluded that PLC δ4 regulates the liver regeneration in cooperation with nuclear PKC α and ε.

knockout mouse, liver regeneration, partial hepatectomy, phospholipase Cδ4, protein kinase C

BrdU, 5-bromo-2′-deoxy-uridine, chromatin, chromatin-rich fraction, DG, diacylglycerol, DMSO, dimethylsulphoxide, PH, partial hepatectomy, PLC, phosphoinositide-specific phospholipase C, PLC δ4^−/−, PLC δ4 gene knockout mouse, PLC δ4^+/+, wild mouse, PKC, protein kinase C, PI, phosphatidylinositol, RT-PCR, reverse-transcription polymerase chain reaction