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Query: UNIPROT:P51812 (mitogen-activated protein)
 10,636 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have studied the role of mitogen-activated protein (MAP) kinases in fetal hepatocyte growth in vitro and in vivo. With myelin basic protein (MBP) as the phosphate acceptor, kinase activity in cultured fetal hepatocyte lysates increased fourfold after exposure to transforming growth factor-alpha (TGF-alpha) for 10 min. This TGF-alpha-responsive MBP kinase activity was accounted for by five distinct MAP kinase isoforms detected by Western immunoblotting. All had negligible activity in cultured fetal hepatocytes under basal conditions. Treatment of fetal hepatocytes with hepatocyte growth factor led to activation of the predominant isoforms, relative molecular weight (M(r)) = 42,000 and 44,000 in a manner indistinguishable from TGF-alpha, whereas insulin had no effect. All five of the immunoreactive MAP kinases were present in both fetal and adult liver homogenates. The M(r) = 42,000 and 44,000 isoforms were only minimally activated in vivo. We conclude that the mitogen-independent growth exhibited by fetal hepatocytes in primary culture is not associated with tonic activation of the MAP kinase system. Our data support the possibility that fetal hepatic growth may be, in part, independent of the action of growth factors as mediated via the MAP kinase system.
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PMID:In vitro and in vivo regulation of hepatic mitogen-activated protein kinases in fetal rats. 781 Jun 54

Perturbations of fetal growth produce parallel but disproportionate changes in fetal liver growth that correlate with circulating fetal insulin concentration. We have studied the effects of insulin and two hepatotrophic factors, transforming growth factor-alpha (TGF alpha) and hepatocyte growth factor (HGF), on DNA synthesis by fetal and adult rat hepatocytes in primary culture. Using serum-free Minimum Essential Medium, fetal hepatocytes synthesized DNA without growth factors, unlike adult hepatocytes. Insulin augmented fetal hepatocyte DNA synthesis after 16-24 h in culture. In contrast, TGF alpha or HGF maximally stimulated fetal hepatocyte DNA synthesis after 40 h in culture. Insulin and TGF alpha were not synergistic in stimulating fetal hepatocyte DNA synthesis, but were synergistic in their action on adult hepatocytes. Brief (10-min) exposure of fetal hepatocytes to TGF alpha or HGF, but not insulin, activated mitogen-activated protein kinases 4-fold. Prolonged (24-h) exposure to TGF alpha or HGF abolished the ability of either to activate mitogen-activated protein kinases, whereas insulin had no effect. Maternal fasting for 48 h before isolation and culturing of fetal hepatocytes abolished the in vitro stimulation of DNA synthesis by insulin without affecting TGF alpha action. We conclude that insulin has growth-promoting actions on fetal hepatocytes that are distinct and independent from those of TGF alpha of HGF.
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PMID:Evidence for a direct hepatotrophic role for insulin in the fetal rat: implications for the impaired hepatic growth seen in fetal growth retardation. 829 72

Asbestos fibers are human carcinogens with undefined mechanisms of action. In studies here, we examined signal transduction events induced by asbestos in target cells of mesothelioma and potential cell surface origins for these cascades. Asbestos fibers, but not their nonfibrous analogues, induced protracted phosphorylation of the mitogen-activated protein (MAP) kinases and extracellular signal-regulated kinases (ERK) 1 and 2, and increased kinase activity of ERK2. ERK1 and ERK2 phosphorylation and activity were initiated by addition of exogenous epidermal growth factor (EGF) and transforming growth factor-alpha, but not by isoforms of platelet-derived growth factor or insulin-like growth factor-1 in mesothelial cells. MAP kinase activation by asbestos was attenuated by suramin, which inhibits growth factor receptor interactions, or tyrphostin AG 1478, a specific inhibitor of EGF receptor tyrosine kinase activity (IC50 = 3 nM). Moreover, asbestos caused autophosphorylation of the EGF receptor, an event triggering the ERK cascade. These studies are the first to establish that a MAP kinase signal transduction pathway is initiated after phosphorylation of a peptide growth factor receptor following exposure to asbestos fibers.
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PMID:Asbestos causes stimulation of the extracellular signal-regulated kinase 1 mitogen-activated protein kinase cascade after phosphorylation of the epidermal growth factor receptor. 896 79

Stimulation of cell proliferation by mitogens involves tyrosine phosphorylation of proteins at the cell membrane by receptor tyrosine kinases. This promotes formation of multi-protein complexes that can activate the small G-protein, Ras. Activation of Ras, in turn, leads to sequential activation of the following three serine-threonine kinases: Raf, extracellular signal-regulated kinase kinase (MEK), and members of the family of mitogen-activated protein (MAP) kinases. Prior studies have shown that intraperitoneal injection of epidermal growth factor (EGF) leads to rapid activation of hepatic MAP kinases in adult rats but not in late gestation (E19) fetal rats (Boylan, J. M., and Gruppuso, P. A. (1996) Cell Growth & Differ. 7, 1261-1269). The present studies were undertaken to determine the mechanism for this "uncoupling" of the MAP kinase pathway. E19 fetal rats and adult male rats were injected with EGF (0.5 microg/g body weight, intraperitoneally) or with saline. After 15 min, livers were removed and prepared for kinase analyses. EGF injection led to a rapid and marked activation of hepatic Raf and MEK in both fetal and adult rats, whereas MAP kinase activation was minimal in fetal as opposed to adult rats. Examination of the ontogeny of this dissociation of MAP kinase activation from MEK activation showed gradual acquisition of intact signaling as an adult hepatocyte phenotype was attained during the first 4 postnatal weeks. Over this period, MAP kinase content as determined by Western immunoblotting was constant. Recombination experiments using partially purified fetal and adult rat liver MEK and MAP kinase showed intact MAP kinase activation in vitro, indicating that neither enzyme was irreversibly altered in the fetus. In studies using primary cultures of E19 fetal rat hepatocytes, uncoupling of MAP kinase activation from MEK activation could be induced by incubation of fetal hepatocytes for 24 h with a potent fetal hepatocyte mitogen, transforming growth factor-alpha. These findings indicate that a novel negative feedback mechanism for MAP kinase regulation may be active in developing rat hepatocytes.
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PMID:Uncoupling of hepatic, epidermal growth factor-mediated mitogen-activated protein kinase activation in the fetal rat. 945 12

Although aging enhances expression and tyrosine kinase activity of epidermal growth factor receptor (EGFR) in the gastric mucosa, there is no information about EGFR signaling cascades. We examined the age-related changes in mitogen-activated protein kinases (MAPKs) [extracellular signal-related kinases (ERKs), c-Jun NH(2)-terminal kinases (JNKs), and p38], an EGFR-induced signaling cascade, and activator protein-1 (AP-1) and nuclear factor-kappaB (NF-kappaB) transcriptional activity in the gastric mucosa of 4- to 6-, 12- to 14-, and 22- to 24-mo-old Fischer 344 rats. AP-1 and NF-kappaB transcriptional activity in the gastric mucosa rose steadily with advancing age. This can be further induced by transforming growth factor-alpha. The age-related activation of AP-1 and NF-kappaB in the gastric mucosa was associated with increased levels of c-Jun, c-Fos, and p52, but not p50 or p65. Total and phosphorylated IkappaBalpha levels in the gastric mucosa were unaffected by aging. Aging was also associated with marked activation of ERKs (p42/p44) and JNK1. In contrast, aging decreased p38 MAPK activity in the gastric mucosa. Our observation of increased activation of ERKs and JNK1 in the gastric mucosa of aged rats suggests a role for these MAPKs in regulating AP-1 and NF-kappaB transcriptional activity. These events may be responsible for the age-related rise in gastric mucosal proliferative activity.
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PMID:Induction of transcriptional activity of AP-1 and NF-kappaB in the gastric mucosa during aging. 1085 14

The bronchial epithelium is a potential source of growth factors that could mediate airway fibrosis during the progression of diseases such as asthma and chronic bronchitis. We report that conditioned medium (CM) from normal human bronchial epithelial cells (NHBECs) contains mitogenic activity for human lung fibroblasts that is blocked by the epidermal growth factor receptor (EGF-R) tyrosine kinase inhibitor AG1478 and by neutralizing antibodies raised against heparin-binding epidermal growth factor-like growth factor (HB-EGF). Neutralizing antibodies against other EGF-R ligands (EGF and transforming growth factor-alpha) or other antibodies against growth factors (platelet-derived growth factors, insulin-like growth factor-1) had no affect on the mitogenic activity of NHBEC-CM. HB-EGF messenger RNA (mRNA) expression in NHBEC was detected by reverse transcriptase/polymerase chain reaction and Northern blot analysis. HB-EGF protein was detected by enzyme-linked immunosorbent assay. Vanadium pentoxide (V2O5), a fibrogenic metal associated with occupational asthma, caused a several-fold increase in HB-EGF mRNA expression and protein, whereas the inert metal titanium dioxide had no effect on HB-EGF expression. V2O5-induced HB-EGF mRNA expression was inhibited by the EGF-R tyrosine kinase inhibitor AG1478, the p38 mitogen-activated protein (MAP) kinase inhibitor SB203580, and the MAP kinase kinase inhibitor PD98059. Finally, HB-EGF induced the production of fibroblast growth factor (FGF)-2 by human lung fibroblasts and anti-FGF-2 antibody partially blocked the mitogenic activity of NHBEC-CM on fibroblasts. These data suggest that HB-EGF is a fibroblast mitogen produced by NHBECs and that induction of an FGF-2 autocrine loop in fibroblasts by HB-EGF accounts for part of this mitogenic activity.
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PMID:Vanadium stimulates human bronchial epithelial cells to produce heparin-binding epidermal growth factor-like growth factor: a mitogen for lung fibroblasts. 1115 45

Phosphorylation of extracellular signal-regulated kinases (ERK1/ERK2) has been implicated in cell proliferation of mammalian cells. In the present study, we investigated the role of docosahexaenoic acid (DHA) in the modulation of ERK1/ERK2 phosphorylation, stimulated either with phorbol 12-myristate 13-acetate (PMA) or transforming growth factor-alpha (TGFalpha) in NIH/3T3 cells. We observed that both PMA and TGFalpha induced ERK1/ERK2 phosphorylation within 5 min of stimulation. PMA acts upstream of MEK and via activation of protein kinase C (PKC), as GF109203X, a potent PKC inhibitor, and U0126, a MEK inhibitor, abolished its actions on ERK1/ERK2 phosphorylation. TGFalpha did not act via PKC because GF109203X failed to curtail the degree of ERK1/ERK2 phosphorylation in these cells. DHA alone failed to induce the phosphorylation of these mitogen-activated protein (MAP) kinases; however, this fatty acid significantly curtailed the PMA- but not TGFalpha-induced MAP kinase enzyme activity and phosphorylation in NIH/3T3 cells. Furthermore, we observed that DHA significantly inhibited PMA-induced translocation of two PKC isoforms, PKC alpha and PKC epsilon, from cytosol to plasma membrane. Interestingly, DHA failed to inhibit the PMA-induced translocation PKC delta isoform in these cells. Furthermore, DHA decreased PMA-induced proliferation of NIH/3T3 cells. In this study, we show for the first time that DHA inhibits MAP kinase ERK1/ERK2) activation and proliferation of NIH/3T3 cells via its inhibitory action on PKC alpha and epsilon isoforms.
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PMID:Docosahexaenoic acid modulates phorbol ester-induced activation of extracellular signal-regulated kinases 1 and 2 in NIH/3T3 cells. 1159 32

Tumor necrosis factor-alpha converting enzyme (TACE) is a prototype member of the adamalysin family of transmembrane metalloproteases that effects ectodomain cleavage and release of many transmembrane proteins, including transforming growth factor-alpha. Growth factors that act through tyrosine kinase receptors, as well as other stimuli, induce shedding through activation of the Erk mitogen-activated protein (MAP) kinase pathway without the need of new protein synthesis. How MAP kinase regulates shedding by TACE is not known. We now report that the cytoplasmic domain of TACE is phosphorylated in response to growth factor stimulation. We also identified a naturally expressed smaller polypeptide corresponding to most of the cytoplasmic domain of TACE. This protein, which we named SPRACT, is derived through alternative translation of the TACE-coding sequence and is, similarly to TACE, phosphorylated in response to growth factor and phorbol 12-myristate 13-acetate stimulation. Phosphoamino acid analysis revealed that growth factor-induced phosphorylation of TACE occurs only on serine and not on threonine or tyrosine. Tryptic mapping experiments coupled with site-directed mutagenesis identified Ser(819) as the major target of growth factor-induced phosphorylation, whereas Ser(791) undergoes dephosphorylation in response to growth factor stimulation. The phosphorylation of Ser(819), but not the dephosphorylation of Ser(791), depends on activation of the Erk MAP kinase pathway. Increased SPRACT expression or mutation of the TACE cytoplasmic domain to inactivate growth factor-induced phosphorylation did not detectably affect growth factor-induced shedding of transmembrane transforming growth factor-alpha by TACE. The roles of SPRACT and the cytoplasmic phosphorylation of TACE remain to be defined.
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PMID:Characterization of growth factor-induced serine phosphorylation of tumor necrosis factor-alpha converting enzyme and of an alternatively translated polypeptide. 1262 Oct 58

Interference with the activation of growth factor receptors, specifically epidermal growth factor receptor (EGFR), represents a promising strategy for the development of novel and selective anticancer therapies. We reported that EGFR-related peptide (ERRP), a recently isolated negative regulator of EGFR, could be a potential therapeutic agent for colorectal cancer. To determine whether ERRP could potentially be a therapeutic agent for prostate carcinoma, we examined the effect of recombinant ERRP on the growth of the prostate cancer cell line PC-3 in vitro. Events of the EGFR signal transduction pathways were also examined. ERRP caused a marked inhibition of cell growth in a dose- and time-dependent manner and also induced apoptosis. The latter was evidenced by increased number of apoptotic cells, activation of caspase-3, and cleavage of poly(ADP-ribose)polymerase. The transforming growth factor-alpha-induced stimulation of cell growth and activation of EGFR was also inhibited by ERRP. These changes were accompanied by a concomitant attenuation of activation of Akt and mitogen-activated protein kinases as well as basal and transforming growth factor-alpha-induced activation of nuclear factor-kappaB. Inhibition of EGFR activation by ERRP could be partly attributed to increased sequestration of EGFR ligands. In summary, our data show that ERRP inhibits the growth of prostate cancer cells by attenuating EGFR signaling processes. ERRP could potentially be an effective therapeutic agent for prostate cancer.
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PMID:Epidermal growth factor receptor-related peptide inhibits growth of PC-3 prostate cancer cells. 1712 43

We investigated the effects of branched-chain amino acids on DNA synthesis and proliferation in primary cultures of adult rat hepatocytes. Of the branched-chain amino acids, only leucine (10(-5)-10(-3) M) induced hepatocyte DNA synthesis and proliferation in a time- and dose-dependent manner. The addition of valine or isoleucine on its own had no significant effects on the hepatocyte DNA synthesis and proliferation. When combined, isoleucine competitively antagonized leucine-stimulated hepatocyte mitogenesis. U73122 (10(-6) M), AG1478 (10(-7) M), wortmannin (10(-7) M), PD98059 (10(-6) M) and rapamycin (10 ng/ml) inhibited the ability of leucine to stimulate the hepatocyte DNA synthesis and proliferation, suggesting that phospholipase C, tyrosine kinase, phosphatidylinositol 3-kinase, mitogen-activated protein (MAP) kinase, and p70 S6 kinase are involved in leucine signaling. The mitogenic effects of leucine are completely abolished by the addition of anti-transforming growth factor-alpha (TGF-alpha) antibody to the culture medium. Furthermore, leucine stimulated TGF-alpha secretion into the culture medium and the leucine effect was inhibited by U73122. Isoleucine alone had no significant effect on TGF-alpha secretion but this agent blocked leucine-induced TGF-alpha secretion. The results suggest that leucine triggers TGF-alpha secretion through a putative leucine receptor. The secreted TGF-alpha then stimulates hepatocyte DNA synthesis and proliferation through activation of TGF-alpha receptor to induce tyrosine kinase/MAP kinase activity and other downstream growth-related signal transducers.
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PMID:Effects of branched-chain amino acids on DNA synthesis and proliferation in primary cultures of adult rat hepatocytes. 1576 40


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