Search

The wnt/beta-catenin pathway plays an important role in liver biology. Because of its diverse roles in liver, it is critical to identify novel targets, which might dictate such roles. Using ?-catenin conditional knockout mice (KO), we identified regucalcin as a novel target of this pathway. Regucalcin is a Ca2+ binding protein, which regulates Ca2+ transport from cytoplasm to nucleus in regenerating liver. mRNA expression of regucalcin was downregulated over 35-fold in KO as compared to wild-type controls (WT), which was confirmed by RT-PCR. An analysis of regucalcin protein expression by Western blotting showed the presence of regucalcin in WT at 1, 3 & 6 months, whereas it was decreased by 1 month and absent after 3 months in KO. Immunohistochemistry confirmed normal expression of regucalcin protein in nucleus and cytosol of WT hepatocytes, which was markedly diminished in KO. Also, beta-catenin overexpressing mice showed elevated levels of regucalcin as compared to the WT. An analysis of the promoter region of mouse regucalcin gene revealed at least 3 putative Tcf-binding sites. Finally, regucalcin protein expression mirrors that of beta-catenin nuclear translocation following 2/3 partial hepatectomy in the mouse. Also, higher regucalcin levels were observed in HepG2 (active-beta-catenin) as compared to Hep3B (normal beta-catenin) hepatoma cells, suggesting a possible link between beta-catenin and regucalcin in beta-catenin-active HCCs. In conclusion, regucalcin is regulated by beta-catenin in the liver, and may play a role in liver regeneration and tumorigenesis. [ABSTRACT FROM AUTHOR]