Additive and Inhibitory Effects of Simultaneous Treatment with Growth Factors on DNA Synthesis through MAPK Pathway and G1 Cyclins in Rat Hepatocytes

Moriuchi, Akihiro; Hirono, Shuichi; Ido, Akio; Ochiai, Toshimasa; Nakama, T.; Uto, Hirofumi; Hori, Takeshi; Hayashi, Katsuhiro; Tsubouchi, Hirohito

doi:10.1006/bbrc.2000.4063

Cited by 44 publications

(45 citation statements)

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“…In addition, mitogen-activated protein kinase (MAPK) is now known to be activated in response to a large number of mitogenic stimuli, and the enzyme is a key participant in the response to various growth factors and cytokines (12,16). In order to better understand the HGF-mediated signaling pathway, we investigated whether activation of MAPK isoforms, ERK1 and ERK2, is involved in HGF-induced DNA synthesis and proliferation in primary cultures of adult rat hepatocytes.…”

Section: Introductionmentioning

confidence: 99%

Activation of Mitogen-Activated Protein Kinase by Hepatocyte Growth Factor Is Stimulated by Both α1- and β2-Adrenergic Agonists in Primary Cultures of Adult Rat Hepatocytes

2007

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Abstract. We investigated the effects of α 1 -and β 2 -adrenergic agonists on hepatocyte growth factor (HGF)-stimulated mitogen-activated protein kinase (MAPK) isoforms in primary cultures of adult rat hepatocytes. Hepatocytes were isolated and cultured with HGF (5 ng / ml) and / or α-and β-adrenergic agonists. Phosphorylated MAPK isoforms (p42 and p44 MAPK) were detected by Western blotting analysis using anti-phospho-MAPK antibody. The results show that HGF increased phosphorylation of p42 MAPK by 2.2-fold within 3 min. The HGF-induced MAPK activation was abolished by AG1478 treatment (10 −7 M). The MEK (MAPK kinase) inhibitor PD98059 (10 −6 M) completely inhibited the HGF-dependent increase in MAPK activity. Phenylephrine (10 −6 M) and metaproterenol (10 −6 M) alone had no effect in the absence of HGF, but significantly increased p42 MAPK induction by HGF. Moreover, the cell-permeable cAMP analog, 8-bromo cAMP (10 −7 M), and phorbol 12-myristate 13 acetate (10 −7 M) potentiated HGFinduced MAPK phosphorylation. The effects of these analogs were antagonized by the protein kinase A (PKA) inhibitor H-89 (10 −7 M) and the protein kinase C (PKC) inhibitor sphingosine (10 −6 M), respectively. These results suggest that direct or indirect activation of both PKA and PKC represent a positive regulatory mechanism for stimulating MAPK induction by HGF.

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Section: Introductionmentioning

confidence: 99%

Activation of Mitogen-Activated Protein Kinase by Hepatocyte Growth Factor Is Stimulated by Both α1- and β2-Adrenergic Agonists in Primary Cultures of Adult Rat Hepatocytes

2007

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“…4,5,[13][14][15] However, there have been few studies regarding the PDGF-induced activation of ERK isoforms and cross- Freshly isolated hepatocytes were plated at a density of 3.3ϫ10 4 cells/cm 2 and cultured as described in the legend to Fig. 1.…”

Section: Discussionmentioning

confidence: 99%

“…The present results are consistent with reports that ERK2 acts upstream of mTOR/p70S6K and downstream of receptor tyrosine kinase, PLC and PI3K in primary cultures of adult rat hepatocytes and cancer cell lines. 11,14,41) In addition, GF109203X-sensitive PKC is not involved in the PDGF signaling pathway. 42) There have been very few studies on the adrenergic agonist-induced regulation of ERK activity.…”

Section: Discussionmentioning

confidence: 99%

“…12,14,15) To better understand the PDGFmediated signaling pathway, we investigated whether activation of ERK isoforms, ERK1 and ERK2, is involved in PDGF-induced DNA synthesis and proliferation in primary cultures of adult rat hepatocytes.…”

Section: )mentioning

confidence: 99%

“…11) In addition, extracellular-signal regulated kinase (ERK)1/2, which is the same as mitogen-activated protein kinase (p42 and p44 MAPK), is now known to be activated in response to a large number of mitogenic stimuli, and the enzyme is a key participant in the response to various growth factors and cytokines. 12,14,15) To better understand the PDGFmediated signaling pathway, we investigated whether activation of ERK isoforms, ERK1 and ERK2, is involved in PDGF-induced DNA synthesis and proliferation in primary cultures of adult rat hepatocytes.…”

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Activation of Extracellular-Signal Regulated Kinase by Platelet-Derived Growth Factor Is Potentiated by Phenylephrine in Primary Cultures of Adult Rat Hepatocytes

Moteki

Kimura

Ogihara

2011

Biological & Pharmaceutical Bulletin

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Platelet-derived growth factor (PDGF) is a potent stimulator of the proliferation by connective tissue cells, such as fibroblasts, smooth muscle cells and hepatic stellate cells, [1][2][3][4] and may play a role in liver regeneration.5) PDGF-BB is reported to induce smooth muscle cells proliferation and cell migration more effectively than PDGF-AA or -AB. [1][2][3][4] PDGF appears to trigger liver regeneration after partial hepatectomy and chemical-induced acute liver cell necrosis in vivo. 6,7) The response of adult rat hepatocytes to PDGF has also been investigated extensively with respect to DNA synthesis and proliferation in vitro. 8,9) The receptor for PDGF, similarly to the receptors for epidermal growth factor (EGF), insulin and hepatocyte growth factor (HGF), contains intrinsic tyrosine kinase activity. The mitogenic effects of PDGF are reportedly mediated through the activation of tyrosine kinase-linked receptors.10) However, little is known about which of the signals originating in the plasma membrane are involved in the induction of hepatocyte DNA synthesis and proliferation by PDGF. We recently reported that PDGF is able to rapidly stimulate hepatocyte DNA synthesis and proliferation during short-term culture.11) In addition, the hepatocyte DNA synthesis and proliferation produced by PDGF was not inhibited depending on initial plating density. Furthermore, we found that hepatocyte DNA synthesis and proliferation by PDGF were potentiated by both a 1 -adrenergic agonists, but not b 2 -adrenergic agonists. 11)More recently, the signal transduction pathways activated in response to PDGF in hepatocytes and other cell types have become more clearly understood. 4,12,13) Using specific inhibitors of signal transducers, we pharmacologically demonstrated that receptor tyrosine kinase, phosphoinositide 3-kinase (PI3K), phospholipase C (PLC) and ribosomal p70 S6 kinase (p70S6K) activities are essential for PDGF-induced DNA synthesis and proliferation in primary cultures of adult rat hepatocytes. 11)In addition, extracellular-signal regulated kinase (ERK)1/2, which is the same as mitogen-activated protein kinase (p42 and p44 MAPK), is now known to be activated in response to a large number of mitogenic stimuli, and the enzyme is a key participant in the response to various growth factors and cytokines. 12,14,15) To better understand the PDGFmediated signaling pathway, we investigated whether activation of ERK isoforms, ERK1 and ERK2, is involved in PDGF-induced DNA synthesis and proliferation in primary cultures of adult rat hepatocytes.On the other hand, 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 receptor; b 1 -and b 2 -adrenergic receptors stimulate adenylate cyclase, while a 2 -adrenergic receptors inhibit its activity.16) a 1 -Adrenergic receptors are related to phospholipase C (PLC) activation and subsequent increases in inos...

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Transforming growth factor β‐1 and amphiregulin act in synergy to increase the production of urokinase‐type plasminogen activator in transformed breast epithelial cells

Giusti

Desruisseau

et al. 2003

Intl Journal of Cancer

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Key words: amphireguline; transforming growth factor-␤1; urokinase-type plasminogen activator; breast cancerNormal and malignant mammary epithelial cells synthesize locally acting growth factors that function through autocrine, juxtacrine or paracrine pathways. Epidermal growth factor (EGF)-related peptides, in combination with their cognate receptors, are involved in the regulation of mammary-gland development, morphogenesis and lactation, and also play a pivotal role in the pathogenesis of human breast cancer. 1 Among growth factors known to be engaged in tissue growth and differentiation, amphireguline (AR) seems to play a special physio-pathological role in the human mammary gland. Amphireguline is a heparin-binding epidermal growth factor-related peptide presenting 38% sequence homology with EGF. It was initially purified from conditioned medium of breast cancer epithelial MCF-7 cells treated with phorbol 12-myristate 13-acetate. 2 Two mature forms of the protein (78 and 84 amino acids) derived from a 252 amino acid transmembrane precursor by proteolytic cleavage are described currently. 3 Both forms have a Mr ranging from 16 -25 kDa, depending on their degree of glycosylation as well as on their NH2-terminal processing. 4 Whereas AR has been demonstrated to bind and to activate EGF-receptor (c-erb B1), direct interaction of AR with other members of the c-erb B family such as c-erb B 2, 3 or 4, has not been reported. 3,5 AR is expressed in several tissues, such as human ovary, placenta, lung, kidney, stomach and breast 6 -8 and induces variable effects on cell proliferation depending on its concentration and on the nature of target cells. 2,3,6 Nevertheless, increased evidences strongly suggest that AR may function as a potential autocrine growth factor in tumoral as well as in their counterpart normal cells such as, prostatic, 9 colic 7 and mammary epithelial cells. 10 Moreover, overexpression of AR has been detected in several estrogen-responsive and -unresponsive breast cancer cell lines as well as in approximately 80% of human primary breast carcinoma. [11][12][13] These data agree with clinical data demonstrating that AR overexpression in solid tumors such as breast cancer is associated with lymph node infiltration and correlates with poor prognosis. 14,15 Degradation of the extracellular matrix (ECM) is a prerequisite for the formation of new vessels, as well as for invasion and metastasis. The degradation of extracellular matrix proteins is catalyzed by the concerted action of several enzymes, including Type IV collagenase and metalloproteinase (MMP). 16 Plasmin system is a broad spectrum of proteolytic enzymes that degrades several extracellular matrix components, activates other matrix metalloproteinases, and thus exhibits a wide array of physiological and pathological processes, such as tissue growth and remodeling, tumor invasion and metastasis. 17 Plasmin is formed from plasminogen, by the tissue-type plasminogen activator (tPA) or by urokinase-type plasminogen activator (uPA). The activation of...

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Additive and Inhibitory Effects of Simultaneous Treatment with Growth Factors on DNA Synthesis through MAPK Pathway and G1 Cyclins in Rat Hepatocytes

Cited by 44 publications

References 41 publications

Activation of Mitogen-Activated Protein Kinase by Hepatocyte Growth Factor Is Stimulated by Both α1- and β2-Adrenergic Agonists in Primary Cultures of Adult Rat Hepatocytes

Activation of Mitogen-Activated Protein Kinase by Hepatocyte Growth Factor Is Stimulated by Both α1- and β2-Adrenergic Agonists in Primary Cultures of Adult Rat Hepatocytes

Activation of Extracellular-Signal Regulated Kinase by Platelet-Derived Growth Factor Is Potentiated by Phenylephrine in Primary Cultures of Adult Rat Hepatocytes

Transforming growth factor β‐1 and amphiregulin act in synergy to increase the production of urokinase‐type plasminogen activator in transformed breast epithelial cells

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