cAMP stimulates the secretory and proliferative capacity of the rat intrahepatic biliary epithelium through changes in the PKA/Src/MEK/ERK1/2 pathway

Francis, Heather; Glaser, Shannon; Ueno, Yoshiyuki; LeSage, Gene; Marucci, Luca; Benedetti, Antonio; Taffetani, Silvia; Marzioni, Marco; Alvaro, Domenico; Venter, Julie; Reichenbach, Ramona; Fava, Giammarco; Phinizy, Jo Lynne; Alpini, Gianfranco

doi:10.1016/j.jhep.2004.06.009

Cited by 110 publications

(151 citation statements)

References 38 publications

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“…phosphorylation level of ERK1/2. Thus, PD98059 was used to attenuate ERK1/2 activation, consistent with previously published studies regarding signaling transduction (25,34). The present study showed that periodic mechanical stress promotes chondrocyte proliferation, AGC and Col2 gene expression, and also activates ERK1/2.…”

Section: Discussionsupporting

confidence: 88%

Periodic mechanical stress activates MEK1/2-ERK1/2 mitogenic signals in rat chondrocytes through Src and PLCγ1

Huang

Liang

Liu

et al. 2011

Braz J Med Biol Res

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Section: Discussionsupporting

confidence: 88%

Periodic mechanical stress activates MEK1/2-ERK1/2 mitogenic signals in rat chondrocytes through Src and PLCγ1

Huang

Liang

Liu

et al. 2011

Braz J Med Biol Res

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“…4,7,9,10,43 Notably, 17␤-estradiol was recently shown to increase the amount of EBP50 in the nuclear fraction of human airway epithelial cells. 44 In addition, cholangiocyte proliferation is regulated by cyclic AMP, 45 which has also been shown to induce an intracellular redistribution of EBP50 in renal epithelial cells. 46 Present and previous data 7-9,47 raise a number of questions regarding the significance of EBP50 distribution with respect to cellular proliferative status.…”

Section: Discussionmentioning

confidence: 99%

Ezrin-Radixin-Moesin-Binding Phosphoprotein (EBP50), an Estrogen-Inducible Scaffold Protein, Contributes to Biliary Epithelial Cell Proliferation

Fouassier

Rosenberg

Mergey

et al. 2009

The American Journal of Pathology

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Ezrin-radixin-moesin-binding phosphoprotein 50 (EBP50) anchors and regulates apical membrane proteins in epithelia. EBP50 is inducible by estrogen and may affect cell proliferation, although this latter function remains unclear. The goal of this study was to determine whether EBP50 was implicated in the ductular reaction that occurs in liver disease. EBP50 expression was examined in normal human liver, in human cholangiopathies (ie, cystic fibrosis, primary biliary cirrhosis, and primary sclerosing cholangitis), and in rats subjected to bile-duct ligation. The regulation of EBP50 by estrogens and its impact on proliferation were assessed in both bile duct-ligated rats and Mz-Cha-1 human biliary epithelial cells. Analyses of cell isolates and immunohistochemical studies showed that in normal human liver, EBP50 is expressed in the canalicular membranes of hepatocytes and, together with ezrin and cystic fibrosis transmembrane conductance regulator, in the apical domains of cholangiocytes. In both human cholangiopathies and bile duct-ligated rats, EBP50 was redistributed to the cytoplasmic and nuclear compartments. EBP50 underwent a transient increase in rat cholangiocytes after bile-duct ligation, whereas such expression was down-regulated in ovariectomized rats. In addition, in Mz-Cha-1 cells, EBP50 underwent upregulation and intracellular redistribution in response to 17␤-estradiol, whereas its proliferation was inhibited by siRNA-mediated EBP50 knockdown. These results indicate that both the expression and distribution of EBP50 are regulated by estrogens and contribute to the proliferative response in biliary epithelial cells. (Am J

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“…We measured intracellular basal cAMP levels (a key regulatory determinant of cellular proliferation including ductal hyperplasia) 5,36,37 in purified cholangiocytes from normal or BDL rats, which immediately after BDL, were treated with NaCl-or RAMH for 1 week. After purification, cholangiocytes were incubated for 1 h at 371C to restore surface proteins damaged by treatment with proteolytic enzymes.…”

Section: Evaluation Of Cholangiocyte Proliferation and Camp Levelsmentioning

confidence: 99%

“…2,3,5 Although increased cAMP levels sustain cholangiocyte proliferation, decreased cAMP formation results in a reduction of cholangiocyte hyperplasia. 2,3,5 The aminergic peptide histamine is responsible for many functions in the body such as neurogenic functions, inflammatory responses, allergic responses and gastric secretion. [11][12][13] Four G-protein coupled histamine receptors (HRs) (H1R, H2R, H3R and H4R) exist.…”

mentioning

confidence: 99%

“…22 The rationale for studying the role of H3R in the regulation of cholangiocyte growth in BDL rats is first based on the fact that H3R exerts their effects by coupling to Ga i/o proteins with inhibition of adenylyl cyclase, 21,22 a key factor in the regulation of cholangiocyte growth. [1][2][3]5 The aims of our study were to: (i) evaluate the presence of H3R protein in bile ducts from normal and BDL rat liver sections; (ii) study the expression of H3R mRNA in purified cholangiocytes from normal and BDL rats; (iii) determine the in vivo effect of (a) the H3R agonist, (R)-(a)-(À)-methylhistamine dihydrobromide (RAMH), 23,24 (b) the H3 HR antagonist, thioperamide maleate 25,26 and (c) histamine, in the absence or presence of thioperamide maleate, on cholangiocyte proliferation in BDL rats; and (iv) to elucidate, in purified BDL cholangiocytes, the transduction mechanisms by which RAMH regulates the proliferation of these cells.…”

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confidence: 99%

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H3 histamine receptor agonist inhibits biliary growth of BDL rats by downregulation of the cAMP-dependent PKA/ERK1/2/ELK-1 pathway

Francis

Franchitto

Ueno

et al. 2007

Laboratory Investigation

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Histamine regulates many functions by binding to four histamine G-coupled receptor proteins (H1R, H2R, H3R and H4R). As H3R exerts their effects by coupling to Ga i/o proteins reducing adenosine 3 0 , 5 0 -monophosphate (cAMP) levels (a key player in the modulation of cholangiocyte hyperplasia/damage), we evaluated the role of H3R in the regulation of biliary growth. We posed the following questions: (1) Do cholangiocytes express H3R? (2) Does in vivo administration of (R)-(a)-(À)-methylhistamine dihydrobromide (RAMH) (H3R agonist), thioperamide maleate (H3R antagonist) or histamine, in the absence/presence of thioperamide maleate, to bile duct ligated (BDL) rats regulate cholangiocyte proliferation? and (3) Does RAMH inhibit cholangiocyte proliferation by downregulation of cAMP-dependent phosphorylation of protein kinase A (PKA)/extracellular signal-regulated kinase 1/2 (ERK1/2)/ets-like gene-1 (Elk-1)? The expression of H3R was evaluated in liver sections by immunohistochemistry and immunofluorescence, and by real-time PCR in cholangiocyte RNA from normal and BDL rats. BDL rats (immediately after BDL) were treated daily with RAMH, thioperamide maleate or histamine in the absence/presence of thioperamide maleate for 1 week. Following in vivo treatment of BDL rats with RAMH for 1 week, and in vitro stimulation of BDL cholangiocytes with RAMH, we evaluated cholangiocyte proliferation, cAMP levels and PKA, ERK1/2 and Elk-1 phosphorylation. Cholangiocytes from normal and BDL rats express H3R. The expression of H3R mRNA increased in BDL compared to normal cholangiocytes. Histamine decreased cholangiocyte growth of BDL rats to a lower extent than that observed in BDL RAMH-treated rats; histamine-induced inhibition of cholangiocyte growth was partly blocked by thioperamide maleate. In BDL rats treated with thioperamide maleate, cholangiocyte hyperplasia was slightly higher than that of BDL rats. In vitro, RAMH inhibited the proliferation of BDL cholangiocytes. RAMH inhibition of cholangiocyte growth was associated with decreased cAMP levels and PKA/ERK1/2/Elk-1 phosphorylation. Downregulation of cAMP-dependent PKA/ERK1/2/Elk-1 phosphorylation (by activation of H3R) is important in the inhibition of cholangiocyte growth in liver diseases.

show abstract

cAMP stimulates the secretory and proliferative capacity of the rat intrahepatic biliary epithelium through changes in the PKA/Src/MEK/ERK1/2 pathway

Cited by 110 publications

References 38 publications

Periodic mechanical stress activates MEK1/2-ERK1/2 mitogenic signals in rat chondrocytes through Src and PLCγ1

Periodic mechanical stress activates MEK1/2-ERK1/2 mitogenic signals in rat chondrocytes through Src and PLCγ1

Ezrin-Radixin-Moesin-Binding Phosphoprotein (EBP50), an Estrogen-Inducible Scaffold Protein, Contributes to Biliary Epithelial Cell Proliferation

H3 histamine receptor agonist inhibits biliary growth of BDL rats by downregulation of the cAMP-dependent PKA/ERK1/2/ELK-1 pathway

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