Role of the p38 MAP-Kinase Signaling Pathway for Cx32 and Claudin-1 in the Rat Liver

Gap junctions and non-neoplastic liver disease

“…Indeed, hemichannels not only are gap junction building blocks, but also provide a route for communication between the cytoplasm and the extracellular environment [75]. A similar type of channels is formed by pannexins (Panx), that are connexin-like proteins of which three family members have been characterized in humans [76], with Liver tissue from extrahepatic cholestasis patients~ Gap junctions [82,83] Liver tissue from cholelithiasis patients ↓ Gap junctions [84] Liver tissue from rats subjected to bile duct ligation ↓ Gap junctions [27,28] ↓ Gap junctions (ligation) ↑ Gap junctions (recanalization) [29] ↓ Cx32 protein (ligation) ↑ Cx32 protein (recanalization) [33] ↓ Cx32 protein (p38 MAPK-mediated) [32] ↓ GJIC ↓ Cx26 protein ↑ Cx26 mRNA ↓ Cx32 mRNA/protein [30] ↓ Cx26 protein ↓ Cx32 protein ↑ Cx43 protein [31] Liver tissue from rats treated with ethinyl estradiol~ Gap junctions [85] Cx26 protein ↑ Cx32 protein ~ Cx43 protein [31] Liver tissue from rats treated with estradiol valerate ↓ Gap junctions [86] Liver tissue from rats treated with phalloidin ↓ Gap junctions (pericentral) ↓ Cx32 protein [35] ↓ Cx26 protein ↓ Cx32 protein ~ Cx43 protein [31] Liver tissue from cdc42 ↓ Gap junctions [87] Liver tissue from lamprey undergoing biliary atresia ↓ Gap junctions [88] Primary rat hepatocyte doublet cultures exposed to taurolithocholic acid/taurolithocholicsulfate acid/ taurochenodeoxycholic acid ↓ GJIC [36] Normal rat cholangiocyte culture exposed to taurolithocholicsulfate acid ↓ GJIC [36] Liver tissue from rats subjected to choledochocaval fistula -deficient mice Panx1 and Panx2 being expressed in the liver [77]. Both hemichannels and pannexin channels are known to act as pathological pores, though specific information in relation to the liver is scarce [78].…”

“…A handful of early studies described a reversible decrease of the hepatic gap junction number upon bile duct ligation [27][28][29]. Later on, this was repeatedly demonstrated to be accompanied by a rapid drop in amounts of Cx32 mRNA [30] and protein levels [30][31][32][33], a process mediated by the p38 mitogen-activated protein kinase (p38 MAPK) [30]. Hepatic Cx26 immunoreactivity also decreases following bile duct ligation [30,31], though its mRNA content rather increases [30].…”

Connexins as Precocious Markers and Molecular Targets for Chemical and Pharmacological Agents in Carcinogenesis

“…Indeed, Kojima et al showed that decreased Cx32 and claudin-1 (tight junctions) expressions during rat liver regeneration and cholestasis were partly controlled via the p38 MAPkinase signalling pathway without cell growth alteration suggesting that inhibition of GJIC is an independent mechanism of cell proliferation [32]. For example, in a large variety of cell types, the cAMP content is high in the G1 phase and is reduced prior to S Fig.…”

“…content is high in the G1 phase and is reduced prior to S phase entry, correlating with the down-regulation of GJIC at the G1/S transition [33,34]. In the Cx32 knock-out mice, the G0/S transition of cell cycle, and thus the proliferative activity of the hepatocytes of regenerating liver, is not promoted, but the duration of the initiation and termination of DNA synthesis is affected [31][32][33][34][35]. For these authors reduced GJIC does not provide a direct signal for cell growth, but rather allows cell cycle progression upon mitogenic stimulation.…”

Connexin and pannexin (hemi)channels in the liver

“…Proliferation is a rare event in the adult liver, but upon partial hepatectomy, the remaining liver lobes start to grow and the original size becomes restored within a week (Taub, 2004). Cx32 expression was found to increase during early hepatocyte cell cycling, followed by a sharp decline (Traub et al, 1983; Dermietzel et al, 1987; Sugiyama and Ohta, 1990; Miyashita et al, 1991; Kren et al, 1993; Temme et al, 2000; Kojima et al, 2003). Less consistent changes have been reported for Cx26 (Kren et al, 1993; Temme et al, 2000).…”