Differential inhibition of epidermal growth factor signaling pathways in rat hepatocytes by long-term ethanol treatment

Effect of short-term ethanol on the proliferative response of Swiss 3T3 cells to mitogenic growth factors

“…Moreover, ethanol exerts differential effect on the same growth factor depending on the cell type. Although ethanol inhibits the signaling events by EGF in hepatocytes (Higashi and Hoek, 1991;Saso et al, 1997;Zhang and Farrell, 1999), ethanol did not directly interfere with EGF receptor function in mouse BALB/c3T3 cells (Resnicoff et al, 1996). Ethanol inhibited the proliferation of PDGF-stimulated astrocyte, but some studies could not show the inhibitory effect of ethanol on PDGF-induced increases in cell proliferation (Resnicoff et al, 1994;Guizetti and Costa, 1996) and in DNA synthesis (Tomono and Kiss, 1995;DeVito et al, 1997).…”

“…Ethanol might activate those signaling proteins by a pertussis toxinsensitive G-protein-dependent mechanism (Reddy and Shukla, 1996). In most cases, ethanol inhibits growth factor-induced receptor tyrosine autophosphorylation (Thurston, Jr. and Shukla, 1992;Resnicoff et al, 1993Resnicoff et al, , 1994Bhavani et al, 1995), which subsequently interferes with the activation of key down stream signaling mediators including PLC-g1 (Higashi and Hoek, 1991;Thurston, Jr. and Shukla, 1992;Saso et al, 1997;Zhang and Farrell, 1999), IRS-1 (Resnicoff et al, 1994;Bhavani et al, 1995), phosphatidylinositol-3 kinase (Resnicoff et al, 1994), and MAP kinases (Banerjee et al, 1998;Thombes et al, 1998;Seiler et al, 2000), and transcription factors such as c-myc, c-fos, and c-jun (Resnicoff et al, 1993). We also observed an inhibition of EGF-or PDGF-stimulated ERK activity.…”

“…Although long-term ethanol feeding suppresses EGF-induced receptor autophosphorylation in rat hepatocytes, it shows a differential in the inhibition of downstream signaling processes mediated by PLC, Shc, and Grb2 (Saso et al, 1997). In FOCUS hepatocellular carcinoma cells, which overexpress IRS-1, ethanol treatment substantially inhibits IRS-1 and MAP kinase signaling and growth-associated gene expression, but has no effect on Shc phosphorylation, which activates p21ras through an IRS-1 independent pathway (Banerjee et al, 1998).…”

“…The blockage of growth factor-mediated cell proliferation by ethanol in several systems elicits the hypothesis that growth factor-induced signaling processes are targets of ethanol toxicity. Included are adenylate cyclase (Hoek et al, 1992;Williams and Kelly, 1993), protein kinase C (Pandy, 1996), protein tyrosine kinases (Miyakawa et al, 1997, Resnicoff et al, 1993, Thurston and Shukla, 1992, MAPKs (Roivainen et al, 1995;Reddy and Shukla, 1996;Chen et al, 1998;Tombes et al, 1998;Reddy and Shukla, 2000), phospholipase C and D (Higashi and Hoek, 1991;Hoek et al, 1992;Thurston and Shukla, 1992;Saso et al, 1997;Zhang and Farrell, 1999), transcription factors such as NF-κB (Zeldin et al, 1996) and STAT3 (Chen et al, 1997).…”

A Multiscale Computational Approach to Dissect Early Events in the Erb Family Receptor Mediated Activation, Differential Signaling, and Relevance to Oncogenic Transformations

“…Phosphorylation and docking reactions are modeled according to Kholodenko et al;37 the MAP kinase pathway reactions are modeled after Schoeberl et al; 57 Akt and PI3K activation are incorporated into the model as described in Brown et al 7 The similar parameterization and topology in these models allowed us to construct a consistent, stable, and comprehensive system with results in good agreement with published experimental data. 52 Seventeen of these reactions are novel to this work and represent enhanced molecular resolution and detail in EGFR activation, phosphorylation, and docking reactions ( Fig. 1 and Table 2).…”