LOCALIZATION OF CAMP-DEPENDENT SIGNAL TRANSDUCERS IN EARLY RAT-LIVER CARCINOGENESIS

Cyclic AMP (cAMP) is an important regulator of liver growth and differ entiation. The main intracellular cAMP receptor, cAMP-dependent protei n kinase (PKA), consists of two regulatory (R) and two catalytic (C) s ubunits. There are two classes, RI and RII, of the regulatory subunit, giving rise to type I (RI2C2) and type II (RII2C2) PKA. The RI/RII ra tio generally decreases during organ development, and increases during carcinogenesis. Alterations in this ratio have been implicated as an important factor in experimental and clinical carcinogenesis. We have studied the expression of RI alpha, RII alpha, C alpha, and an importa nt substrate of PKA, the cAMP-response element binding protein, during rat liver carcinogenesis. Two-color immunofluorescence and confocal l aser scan microscopy were used to characterize localization of the cAM P-dependent signal transducers in hepatocytes, bile ducts, oval cells, and preneoplastic lesions. We found that bile ducts and oval cells (p utative liver stem cells) contained a higher RI/RII ratio than hepatoc ytes and preneoplastic lesions. Thus, an altered RI/RII ratio was not detected during early rat liver carcinogenesis, but may contribute to differentiation of putative liver stem cells to hepatocytes.