G protein‐coupled receptor agonist‐stimulated expression of ATF3/LRF‐1 and c‐myc and comitogenic effects in hepatocytes do not require EGF receptor transactivation

Abstract

Several agonists acting on G protein-coupled receptors (GPCR) enhance the mitogenic effect of epidermal growth factor (EGF) in rat hepatocytes, through mechanisms that have only partially been clarified. Results in various cells have led to the idea that a major mechanism for GPCR-mediated stimulation of cell growth is transactivation of receptor tyrosine kinases, particularly the EGF receptor (EGFR), leading to rapid phosphorylation of the EGFR and activation of downstream signaling pathways. In the present study cultured rat hepatocytes were exposed to various GPCR agonists, including vasopressin, angiotensin II (Ang.II), norepinephrine, or prostaglandin F(2 alpha) (PGF(2 alpha)). None of these agents increased the phosphorylation of the EGFR or the docking protein Shc. Furthermore, we examined the effect of the GPCR agonists on the expression of two early response genes believed to be involved in growth activation. The GPCR agonists increased the mRNA expression of c-myc, and also of activating transcription factor 3 (ATF3)/liver regeneration factor-1 (LRF-1), which is a novel finding. Finally, the selective EGFR inhibitor AG1478 did not suppress the activation of extracellular signal-regulated kinase 1/2 (ERK1/2) or the induction of c-myc or ATF3/LRF-1 by the GPCR agonists, and did not prevent the comitogenic effects induced by these agents, while it blocked the effect of EGF on these responses. The results suggest that GPCR agonists induce expression of ATF3/LRF-1 and c-myc and exert comitogenic effects through mechanisms that do not require EGFR transactivation.

Prostaglandins Enhance Epidermal Growth Factor-Induced DNA Synthesis in Hepatocytes by Stimulation of E Prostanoid 3 and F Prostanoid Receptors

“…This is in agreement with our previous observation that cAMP does not mediate the proliferative effects of prostaglandins in the hepatocytes (Refsnes et al, 1995). Furthermore, although EP4 receptors have been found to stimulate cyclin D1 expression and phosphorylation of EGF receptor and extracellular signal-regulated kinase in murine hepatocytes (Kataoka et al, 2005), prostaglandins do not transactivate the EGF receptor in rat hepatocytes (Nilssen et al, 2004) but act to enhance subsequent stimulation of extracellular signal-regulated kinase and Akt by EGF (Dajani et al, 2007). In addition, we found no additive effects between sulprostone and misoprostol on DNA synthesis, suggesting lack of involvement of EP4 receptors.…”

Oxidative Stress-Responsive Transcription Factor ATF3 Potentially Mediates Diabetic Angiopathy

“…While ATF3 was reported to suppress cell growth in HeLa cells by blocking G 1 -S progression (9), there have been at least four studies that showed growth-promoting activity of ATF3 (2,29,33,41). ATF3 was found to be downstream of c-Myc and adenovirus-mediated overexpression of ATF3 in c-Mycdeficient fibroblasts resulted in increased CDK4 and CDK2 activity (41).…”

Mechanisms of endothelin-1-induced MAP kinase activation in adrenal glomerulosa cells

“…For example, MMP levels are low in normal liver, but many-fold higher in hepatocellular carcinomas (20). Hence, MAPK activation by a GPCR agonist, angiotensin II, is dependent on MMP-mediated transactivation of the EGF-R in clonal C9 hepatic cells (38), but is independent of these proteins in native rat hepatocytes (24,48). Similarly, PI3K/Akt activity is high in H295R cells derived from human adrenal cortical carcinoma tissue, but low in primary cultures of BAG cells (54).…”