Bidirectional concentration-dependent effects of glucagon and dibutyryl cyclic AMP on DNA synthesis in cultured adult rat hepatocytes

Brønstad, Gunnar; Sand, Tor‐Erik; Christoffersen, Thoralf

doi:10.1016/0167-4889(83)90025-3

Cited by 52 publications

(9 citation statements)

References 19 publications

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“…[49][50][51] Cyclic AMP can either stimulate or inhibit DNA synthesis depending on culture conditions. [51][52][53] For example, Crespo et al reported that isoproterenol treatment of COS-7 cells had an acute stimulatory and chronic inhibitory effect on ERK2 activity, the former being mediated by G protein bg subunits and the latter by G protein a subunit via PKA.…”

Section: Discussionmentioning

confidence: 99%

Activation of Extracellular-Signal Regulated Kinase by Epidermal Growth Factor Is Potentiated by cAMP-Elevating Agents in Primary Cultures of Adult Rat Hepatocytes

Moteki

Kimura

Ogihara

2011

Biological & Pharmaceutical Bulletin

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Epidermal growth factor (EGF) is well recognized as a potent mitogen, and appears to trigger liver regeneration after partial hepatectomy or after acute liver cell necrosis caused by chemicals in vivo. [1][2][3][4] The response of adult rat hepatocytes to EGF has also been extensively investigated with respect to DNA synthesis and proliferation in vitro. EGF is now known to be a potent hepatocyte mitogen and induces multiple biological activities in a wide variety of cell types. [5][6][7][8] More recently, we reported that EGF rapidly stimulates hepatocyte DNA synthesis and proliferation during short-term (e.g., 4 h) culture.9) In addition, the hepatocyte DNA synthesis and proliferation induced by EGF was inhibited depending on the initial plating density. Furthermore, we found that EGF-induced hepatocyte DNA synthesis and proliferation were potentiated by b 2 -adrenergic agonists. 9)The signal transduction pathways activated in response to EGF in hepatocytes and other cell types are now more clearly understood. [10][11][12] Using specific inhibitors of signal transducers, we pharmacologically demonstrated that EGF-receptor tyrosine kinase and ribosomal p70 S6 kinase activities, but not phosphoinositide 3-kinase (PI3K), are essential for EGFinduced DNA synthesis and proliferation in primary cultures of adult rat hepatocytes. 9) PI3K is considered to be involved in hepatocyte growth factor (HGF) signal transduction. 13)In addition, extracellular-signal regulated kinase (ERK)1/2, also known as mitogen-activated protein kinase (p42/44 MAPK), is now known to be activated in response to a large number of mitogenic stimuli, and this enzyme is a key participant in the response to various growth factors and cytokines.14,15) In order to better understand the EGF-mediated signaling pathway, we investigated whether activation of the ERK isoforms, ERK1 and ERK2, is involved in EGFinduced DNA synthesis and proliferation in primary cultures of adult rat hepatocytes.Catecholamines (e.g., norepinephrine and its analogs) have been shown to be involved in the regulation of liver function (e.g., lipid metabolism, carbohydrate metabolism and cell growth). There are several types of catecholamine receptors, b 1 -and b 2 -receptors, that stimulate adenylate cyclase (AC), while a 2 -receptor inhibits its phosphorylation. 5,16) a 1 -Receptor is involved in phospholipase C activation and subsequent increases in inositolphosphate turnover and diacylglycerol production.17,18) However, some investigators have reported that a 1 -and b-adrenergic responses are involved in adrenergic regulation of carbohydrate metabolism in the liver of normal adult rats and in cultured hepatocytes. 19,20) There are few studies regarding the adrenergic regulation of ERK1/2 phosphorylation induced by growth factors in liver cells. Therefore, in the present study, we examined whether a 1 -, a 2 -and b 2 -adrenergic agonists can modulate EGF-induced ERK1/2 isoform activities. The physiological significance of crosstalk between the EGF pathway and a 1 -, a 2 -and...

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Section: Discussionmentioning

confidence: 99%

Activation of Extracellular-Signal Regulated Kinase by Epidermal Growth Factor Is Potentiated by cAMP-Elevating Agents in Primary Cultures of Adult Rat Hepatocytes

Moteki

Kimura

Ogihara

2011

Biological & Pharmaceutical Bulletin

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“…Normal hepatocytes have a biphasic response, i.e. stimulation by moderate cAMP and inhibition by strongly elevated cAMP (Br0nstad et al, 1983;Vintermyr et al, 1989;Thoresen et al, 1990). In the regenerating rat liver we have proposed that the prereplicative cAMP surge (MacManus et al, 1972) acts to inhibit the G1/S transition, and that the block in late GI is overcome partly because of the increased R/C ratio occurring prereplicatively (Ekanger et al, 1989).…”

Section: Discussionmentioning

confidence: 99%

Differential expression of cAMP-kinase subunits is correlated with growth in rat mammary carcinomas and uterus

Houge

Cho-Chung²,

Døskeland³

1992

Br J Cancer

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SummaryThe expression of the regulatory (RI and RII) and catalytic (C) subunits of cAMP-dependent protein kinase was found to depend on the growth-state in oestrogen-dependent DMBA-induced mammary adenocarcinomas as well as in uteri of the rat. Castration-induced atrophy of the oestrogen-dependent tissues was accompanied by a decrease of the concentration of regulatory subunits (RI and RII) relative to both the catalytic subunit (C) and total protein, decreasing the R/protein and R/C ratios. A hyperplastic burst caused by high-dose oestrogen-replacement treatment was associated with an increased level of RI and little change in RII and C levels. Only minor differences were noted for the expression of mRNA for the a and P subtypes of RI, RII and C between rat uteri from castrated and oestrogen-treated animals, or between mammary tumours from normal and castrated animals. Expression of RIP-mRNA was detected only in the uterus. Our findings provide an experimental correlate for the reported value of the parameter R/protein in human mammary cancer biopsies to predict prognosis and outcome of therapy. Due to the sensitivity of the R/protein ratio towards changes in extracellular protein content, we recommend the biologically more meaningful R/C ratio in further clinical evaluations of mammary tumour biopsies.

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“…Hepatocytes were isolated as in [26]. For culturing [27], the hepatocytes were washed twice in Dulbecco's Modified Eagle's Medium and seeded in the same medium (5-6 x lo5 cells/ml) supplemented with 15% horse serum, 2.5% fetal calf serum, penicillin (100 units/ml), streptomycin (0.1 mg/ml) and other additions as indicated, using Costar culture flasks of varying size with 0.12 ml medium/cm2.…”

Section: Hepatocyte Isolation and Culturementioning

confidence: 99%

Mechanisms for the emergence of catecholamine‐sensitive adenylate cyclase and β‐adrenergic receptors in cultured hepatocytes

et al. 1983

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Adult male rat hepatocytes, which normally respond poorly to β‐adrenergic agents, acquire such responsiveness during primary monolayer culture. We here show that the rise in catecholamine‐sensitive adenylate cyclase activity in hepatocytes in vitro is closely paralleled by an increase in the ability to bind the β‐adrenoceptor ligand [125I]cyanopindolol. The emergence of β‐adrenergic responsiveness did not require cell attachment or serum. Addition of dexamethasone, insulin, thyroxine or dihydortestosterone to the cultures, singly or in combination, did not prevent the augmented β‐adrenergic responsiveness. The increase in catecholamine‐sensitive adenylate cyclase activity and [125I]cyanopindolol binding could be blocked by cycloheximide or actinomycin D. Exposure of the cultures to isoproterenol at 3‐hourly intervals led to a dose‐dependent suppression of the rise in isoproterenol‐responsive adenylate cyclase and prevented the increase in β‐adrenoceptor binding.

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Bidirectional concentration-dependent effects of glucagon and dibutyryl cyclic AMP on DNA synthesis in cultured adult rat hepatocytes

Cited by 52 publications

References 19 publications

Activation of Extracellular-Signal Regulated Kinase by Epidermal Growth Factor Is Potentiated by cAMP-Elevating Agents in Primary Cultures of Adult Rat Hepatocytes

Activation of Extracellular-Signal Regulated Kinase by Epidermal Growth Factor Is Potentiated by cAMP-Elevating Agents in Primary Cultures of Adult Rat Hepatocytes

Differential expression of cAMP-kinase subunits is correlated with growth in rat mammary carcinomas and uterus

Mechanisms for the emergence of catecholamine‐sensitive adenylate cyclase and β‐adrenergic receptors in cultured hepatocytes

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