Earlier Expression of the Transcription Factor Hfh–11B Diminishes Induction of P21Cip1/Waf1 Levels and Accelerates Mouse Hepatocyte Entry Into S–Phase Following Carbon Tetrachloride Liver Injury

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Abstract
Partial hepatectomy (PH) or toxic liver injury induces the proliferation of terminally differentiated hepatic cells to regenerate the original size of the adult liver. Previous PH liver regeneration studies showed that premature transgenic expression of the Forkhead Box M1b (FoxM1b, HFH–11B) transcription factor accelerated hepatocyte entry into DNA replication (S–phase). In this study, we used carbon tetrachloride (CCl4) liver injury to induce a different type of mouse liver regeneration and show that premature hepatic HFH–11B levels also accelerate the onset of hepatocyte S–phase in this injury model. Unlike PH liver regeneration, earlier hepatocyte proliferation after CCl4 liver injury is correlated with diminished transgenic hepatic levels of p21CIP1/WAF1 at the G1/S transition of the cell cycle. Differential hybridization of cDNA arrays and RNase protection studies determined that CCl4 regenerating liver of transgenic mice displayed early stimulated expression of the S–phase promoting cyclin D1 and cyclin E and sustained levels of Cdc25a phosphatase genes. Compared with previous PH liver regeneration studies, our data suggest that premature expression of HFH–11B activates distinct S–phase promotion pathways in the CCl4 liver injury model. Although proliferating transgenic hepatocytes induced by either PH or CCl4 liver injury displayed early expression of identical M–phase cyclin genes (cyclin B1, B2, A2, and F), only CCl4 regenerating transgenic liver exhibited earlier expression of the M–phase promoting Cdc25b. These studies suggest that CCl4 injury of transgenic liver not only uses the same mechanisms as PH to mediate accelerated hepatocyte entry into mitosis, but also promotes M–phase entry by stimulating Cdc25b expression.

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