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At least 55 records · Page 3Linked to original sources
PubMed1993

Dephosphorylation and inactivation of the mitogen-activated protein kinase by a mitogen-induced Thr/Tyr protein phosphatase.

The activation of extracellular signal-regulated kinase (ERK) or mitogen-activated protein kinase (MAPK) by a dual specific kinase, MEK (MAPK or ERK kinase), is a critical event in the mitogenic signal transduction pathway. However, little is known about the mechanism of ERK inactivation, which occurs after stimulation. In this report, we demonstrated that a dual specific protein phosphatase, HVH1 (human VH1 phosphatase homolog) whose expression is induced by mitogenic growth factors, specifically inactivates ERK. When several phosphoproteins were tested for recombinant HVH1, only MEK-activated ERK1 was dephosphorylated. HVH1 selectively dephosphorylated threonine and tyrosine residues but not serine residues of the activated ERK1. Inactivation of ERK1 by HVH1 could be reversed by MEK, suggesting that HVH1 dephosphorylates the same residues that are recognized and phosphorylated by MEK. Our results suggest that mitogenic growth factors transiently activate ERK (peak at 5 min followed by a rapid decline) by temporally activating MEK (the on signal) and inducing the expression of HVH phosphatase (the off signal).

Base Sequence↗
PubMed1984

Ontogeny of T-cell mitogen response in Lewis rats. III. Juvenile adherent suppressor cells block adult mitogen responses.

Spleen cells from suckling female Lewis rats (4 to 20 days old) were able to suppress mitogenic responses to concanavalin A (Con A) and phytohemagglutinin (PHA) of spleen or thymus cells from adult female Lewis rats and thymus cells from suckling Lewis rats. Thymus cells from suckling rats were unable to suppress adult spleen cell mitogenic responses to Con A. Removal of carbonyl iron (cFe)-, plastic-, or nylon-wool-adherent cells removed the suppressive action of juvenile spleen cells, but irradiation did not. Separated plastic-adherent spleen cells from suckling animals suppressed adult mitogenic responses to Con A. at optimal Con A doses 2-mercaptoethanol (2-ME, 2 X 10(-5) M) abolished the suppressive effect of juvenile cells, however, at the hyperoptimal dose of Con A (125 micrograms/ml) even higher doses of 2-ME did not relieve suppression by juvenile cells. These suppressor cells in suckling pups were affected by early weaning which decreased suppression, resulting in enhanced mitogenic responses of juvenile cells and removal of the ability to suppress adult mitogenic response.

Aging↗
PubMed1997

Protection of rat myocardium by mitogenic and non-mitogenic fibroblast growth factor during post-ischemic reperfusion.

The effects of acidic fibroblast growth factor (FGF-1) and basic fibroblast growth factor (FGF-2) and a non mitogenic form of FGF1 on myocardial ischemia and reperfusion were assessed. Rats underwent 10 minutes of coronary artery occlusion followed by 24 hours of reperfusion. Creatinine kinase content of the affected myocardium showed that both fibroblast growth factors 1 and 2 effectively protected against ischemia reperfusion injury (p < 0.01), and that the vasoactive but nonmitogenic form of the FGF1 was equally protective (p < 0.01 versus control + vehicle). The results were confirmed by light and electron-microscopy histological studies. Histological evaluations after treatment with the non-mitogenic fibroblast growth factor 1 showed that it did not generate the severe hyperplasia and connective tissue disorganization observed with the native mitogenic proteins. The possibility of using a non-mitogenic form of fibroblast growth factor for cardio-protection circumvents many of the potentially undesirable effects that may derive from systemically introducing broad spectrum acting fibroblast growth factors in vivo. This myocardial protection observed 24 hours after the treatment with fibroblast growth factors, and the efficacy of the non-mitogenic form of the protein, also suggest that the protective effect of fibroblast growth factors may be due to the increased blood flow rather than to angiogenesis.

Animals↗
PubMed1988

Mitogenic and non-mitogenic ligands trigger a calcium-dependent cytosolic acidification in human T lymphocytes.

We have investigated the patterns of cytosolic pH and Ca2+ ([Ca2+]i) changes after exposure of human peripheral blood T cells to different mitogenic and non-mitogenic ligands. Using ligands that have different accessory cell requirements and varying effect on [Ca2+]i or cell proliferation, we observed that intracellular acidification occurred only with agents that increased [Ca2+]i. However, treatment of the cells with the phorbol ester, 12-O-tetradecanoylphorbol-13-acetate, results in significant cytosolic alkalinization without detectable acidification, but did not affect the proliferative responses to mitogenic ligands and was a potent co-mitogen with non-mitogenic ligands. These data indicate that initial acidification or alkalinization responses are not essential for early activation or triggering of DNA synthesis.

Antibodies, Monoclonal↗
PubMed1990

Relationship between mitogen receptors in peripheral blood lymphocytes and blastogenic responses to mitogen.

The relationship between the optimum concentration of mitogen which induces lymphocyte blastogenic response and the receptor occupancy by mitogen was investigated. The receptor occupancies which induced maximal blastogenic activity in equine, bovine and canine peripheral blood lymphocytes (PBL) were 31.1 per cent, 26.5 per cent and 38.4 per cent with phytohaemagglutinin-P, and 48.2 per cent, 17.9 per cent and 24.5 per cent with concanavalin A, respectively. The data clearly show that each animal species had its own optimum concentration of mitogen for stimulation of PBL. Optimum concentration for blastogenesis and number of binding sites of each mitogen had a good correlation with each other for all three species.

Animals↗
PubMed2000

Activation of p42/44 and p38 mitogen-activated protein kinases by extracellular calcium-sensing receptor agonists induces mitogenic responses in the mouse osteoblastic MC3T3-E1 cell line.

Recently, substantial evidence has accumulated that the G-protein-coupled, extracellular calcium (Ca(2+)(o))-sensing receptor (CaR) is expressed in bone marrow-derived cells, including osteoblasts, stromal cells, monocytes-macrophages, and osteoclast precursor cells. Our previous studies have shown that the mouse osteoblastic MC3T3-E1 cell line also expresses the CaR and exhibits mitogenic responses when exposed to various CaR agonists. In this study, in order to understand the signaling pathway(s) mediating this response, we studied the effects of CaR agonists on the phosphorylation of p42/44 mitogen-activated protein kinase (MAPK) (Erk1/2), p38 MAPK, and c-Jun N-terminal kinase (JNK) in MC3T3-E1 cells. Raising the level of Ca(2+)(o) (4.5 mM) or addition of the polycationic CaR agonists, gadolinium (Gd(3+)) (25 microM), neomycin (300 microM) or spermine (1 mM), each stimulated phosphorylation of both p42/44 and p38 MAPKs, but not JNK, as assessed using phospho-specific antibodies to the respective MAPKs. Furthermore, phosphorylation of p42/44 and p38 MAPK were markedly inhibited by their selective and potent inhibitors, PD98059 (50 microM) and SB203580 (10 microM), respectively. Finally, the two inhibitors suppressed [(3)H]thymidine incorporation into DNA in MC3T3-E1 cells at a normal level of Ca(2+)(o) (1.8 mM) as well as when stimulated by high (4.5 mM) Ca(2+)(o), Gd(3+), or neomycin. Thus, in mouse osteoblastic MC3T3-E1 cells, both the p42/44 and p38 MAPK cascades play pivotal roles in CaR-stimulated mitogenic responses.

3T3 Cells↗
PubMed2001

Lysophosphatidic acid is an osteoblast mitogen whose proliferative actions involve G(i) proteins and protein kinase C, but not P42/44 mitogen-activated protein kinases.

The simple glycerophospholipid lysophosphatidic acid (LPA) acts both as an intermediary in phospholipid metabolism and as an intercellular signaling molecule in its own right. In various cell types, LPA signals through its membrane-bound, G protein-coupled receptors to influence cellular processes such as proliferation, survival, and cytoskeletal function. Its actions in bone cells have not been studied. Here we show that the LPA receptor, LP(A1)/edg-2/vzg-1, is expressed in primary rat osteoblasts and the UMR 106-01 osteoblastic cell line. LPA potently induces DNA synthesis and an increase in cell number in cultures of osteoblastic cells. LPA rapidly (within 10 min) stimulates phosphorylation of p42/44 mitogen-activated protein (MAP) kinases in osteoblastic cells, an effect that is sensitive to inhibition of G(i) proteins, inhibition of influx of extracellular calcium, and inhibition of protein kinase C. LPA-induced DNA synthesis is partially inhibited by either pertussis toxin or calphostin C, but is insensitive to specific inhibitors of MEK, the kinase upstream of p42/44 MAP kinases, or of phosphatidylinositol-3 kinases. These data demonstrate that LPA is an osteoblast mitogen whose signaling effects in osteoblastic cells include activation of p42/44 MAP kinases. However, the LPA mitogenic signal in osteoblastic cells, while requiring G(i) proteins and protein kinase C, is independent of the activity of p42/44 MAP kinases.

Animals↗
PubMed1994

The astrocyte mitogen, tumor necrosis factor-alpha, inhibits the proliferative effect of more potent adult human astrocyte mitogens, gamma-interferon and activated T-lymphocyte supernatants.

The proliferative response of adult human astrocytes to tumor necrosis factor-alpha (TNF-alpha) was examined. Applied alone, TNF-alpha was dependent on the content of serum in the feeding medium, being mitogenic only in conditions of over 15% serum in medium. In accordance with previous results, supernatants from activated human CD8+ T-lymphocytes (CD8 SN) and recombinant human interferon-gamma (IFN-gamma) enhanced proliferation of adult human astrocytes in 5% serum-containing medium. Simultaneous administration of TNF-alpha (10-1000 units), however, abrogated the mitogenic effects of either CD8 SN or IFN-gamma; the inhibitory effect of TNF-alpha was lost if applied 2 days following IFN-gamma treatment. These studies show that while TNF-alpha is an astrocyte mitogen under selected conditions, it inhibits proliferation induced by other mitogens. In this manner, TNF-alpha may be important in regulating the proliferative response of astrocytes during reactive astrogliosis in vivo.

Adult↗
PubMed2005

Dehydroepiandrosterone negatively regulates the p38 mitogen-activated protein kinase pathway by a novel mitogen-activated protein kinase phosphatase.

Dehydroepiandrosterone-sulfate, the sulfated form of dehydroepiandrosterone, is the most abundant steroid in young adults, but gradually declines with aging. In humans, the clinical application of dehydroepiandrosterone targeting some collagen diseases, such as systemic lupus erythematosus, as an adjunctive treatment has been applied in clinical trial. Here, we report that dehydroepiandrosterone may negatively regulate the mitogen-activated protein kinase pathway in humans via a novel dual specificity protein phosphatase, DDSP (dehydroepiandrosterone-enhanced dual specificity protein phosphatase). DDSP is highly homologous to LCPTP/HePTP, a tissue-specific protein tyrosine phosphatase (PTP) which negatively regulates both ERK and p38-mitogen-activated protein kinase, and is transcribed from the PTPN7 locus by alternative splicing. Although previous reports have shown that the mRNA expression of the LCPTP/HePTP gene was inducible by extracellular signals such as T-cell antigen receptor stimulation, reverse transcribed (RT)-PCR experiments using specific sets of primers suggested that the expression of LCPTP/HePTP was constitutive while the actual inducible sequence was that of DDSP. Furthermore DDSP was widely distributed among different types of human tissues and specifically interacted with p38-mitogen-activated protein kinase. This inducible negative regulation of the p38-mitogen-activated protein kinase-dependent pathway may help to clarify the broad range of dehydroepiandrosterone actions, thereby aiding the development of new preventive or adjunctive applications for human diseases.

Amino Acid Sequence↗
PubMed1990

Changes in inositol lipids and phosphates after stimulation of the MAS-transfected NG115-401L-C3 cell line by mitogenic and non-mitogenic stimuli.

A neuronal cell line (NG115-401L-C3) was stimulated by mitogenic (angiotensin) and non-mitogenic (bradykinin) peptides and examined for the time course of changes in the levels of radiolabelled inositol phosphates and phospholipids. Both peptides stimulated the time-dependent production of Ins(1,4,5)P3 and related metabolites. Bradykinin caused a much larger increase in Ins(1,4,5)P3 than did angiotensin. However, both peptides stimulated similar rises in the levels of Ins(1,3,4)P3 and InsP4. Bradykinin, but not angiotensin, caused a rapid (within 2 s) fall in the levels of PtdIns(4,5)P2 and PtdIns(4)P. Serum pretreatment of the cells caused a 2-3-fold potentiation of both the responses to bradykinin and angiotensin. Although significant levels of PtdIns(3)P were detected in resting cells, neither mitogenic (angiotensin, insulin-like growth factor I, transforming growth factor beta) nor non-mitogenic (bradykinin, nerve growth factor, interleukin-1) receptor activation changed its levels, arguing against regulation of either PtdIns 3-kinase or PtdIns(3)P phosphatase. We conclude that, as judged by the levels of its product. PtdIns(3)P, the enzyme PtdIns 3-kinase is not activated. This questions the significance of this activity in the receptor-mediated initiation of DNA synthesis.

Angiotensin II↗
PubMed1973

The mitogenic effect of lipopolysaccharide on bone marrow-derived mouse lymphocytes. Lipid A as the mitogenic part of the molecule.

Lipopolysaccharides with different structure, isolated from different mutant strains of Escherichia coli and Salmonella bacteria, and chemical degradation products of these lipopolysaccharides have been employed to investigate which part of the lipopolysaccharide molecule exerts mitogenic effects on bone marrow-derived mouse lymphocytes. Within the structure of lipopolysaccharide consisting of lipid A, a core polysaccharide, and the O-polysaccharide antigen, lipid A was found to be the mitogenic part. The mitogenic effect of lipid A, consisting of phosphorylated glucosamine disaccharide units with ester- and amide-linked fatty acids, was lost after alkali treatment, which removes ester-linked fatty acids. Insertion of the lipid A portion of lipopolysaccharides into the lipid bilayer of the plasma membranes of bone marrow-derived lymphocytes is discussed as the initial mitogenic action.

Antibody Formation↗
PubMed1978

In vitro mitogen stimulation of synovial fluid lymphocytes from rheumatoid arthritis and juvenile rheumatoid arthritis patients: dissociation between the response to antigens and polyclonal mitogens.

The in vitro responses to mitogens of synovial fluid lymphocytes obtained from eight patients with rheumatoid arthritis (RA) and eight patients with juvenile rheumatoid arthritis (JRA) were studied. The results were compared to the transformation of the patient's peripheral blood lymphocytes stimulated with the same mitogens. Both RA and JRA synovial fluid lymphocytes showed a low transformation to the polyclonal mitogens PHA and PWM with a low ratio PHA-response/PWM-response. The stimulatory effect of purified protein derivative of tuberculin (PPD) was high, whereas a Candida albicans antigen preparation gave a more variable stimulation of the synovial fluid lymphocytes. In some patients the complete mitogen transformation profile of lymphocytes obtained from synovial fluid, synovial tissue and peripheral blood was studied. The results of the synovial fluid and tissue lymphocytes were similar.

Antigens↗
PubMed1999

Protein kinase Cdelta mediates neurogenic but not mitogenic activation of mitogen-activated protein kinase in neuronal cells.

In several neuronal cell systems, fibroblast-derived growth factor (FGF) and nerve growth factor (NGF) act as neurogenic agents, whereas epidermal growth factor (EGF) acts as a mitogen. The mechanisms responsible for these different cellular fates are unclear. We report here that although FGF, NGF, and EGF all activate mitogen-activated protein (MAP) kinase (extracellular signal-related kinase [ERK]) in rat hippocampal (H19-7) and pheochromocytoma (PC12) cells, the activation of ERK by the neurogenic agents FGF and NGF is dependent upon protein kinase Cdelta (PKCdelta), whereas ERK activation in response to the mitogenic EGF is independent of PKCdelta. Antisense PKCdelta oligonucleotides or the PKCdelta-specific inhibitor rottlerin inhibited FGF- and NGF-induced, but not EGF-induced, ERK activation. In contrast, EGF-induced ERK activation was inhibited by the phosphatidylinositol-3-kinase inhibitor wortmannin, which had no effect upon FGF-induced ERK activation. Rottlerin also inhibited the activation of MAP kinase kinase (MEK) in response to activated Raf, but had no effect upon c-Raf activity or ERK activation by activated MEK. These results indicate that PKCdelta functions either downstream from or in parallel with c-Raf, but upstream of MEK. Inhibition of PKCdelta also blocked neurite outgrowth induced by FGF and NGF in PC12 cells and by activated Raf in H19-7 cells, indicating a role for PKCdelta in the neurogenic effects of FGF, NGF, and Raf. Interestingly, the PKCdelta requirement is apparently cell type specific, since FGF-induced ERK activation was independent of PKCdelta in NIH 3T3 murine fibroblasts, in which FGF is a mitogen. These data demonstrate that PKCdelta contributes to growth factor specificity and response in neuronal cells and may also promote cell-type-specific differences in growth factor signaling.

Acetophenones↗
PubMed1992

Mitogenic effect of zinc on lymphocytes from strains of mice that are either high or low-responder to T-cell mitogens.

We have studied the in vitro mitogenic effect of ZnCl2 in cultures of lymphocytes from Balb/c or C57BL/6 mice which are high-responder or low-responder to T-cell mitogens respectively. Zn induced proliferation of spleen cells from Balb/c mice cultured without 2-ME. Higher levels of proliferation were observed in cultures with 2-ME. In contrast, Zn only induced proliferation of spleen cells from C57BL/6 mice in the presence of 2-ME. No response to Zn was observed in cultures without 2-ME, of spleen cells from either Balb/c or C57BL/6 mice depleted of plastic adherent cells. However, in cultures with 2-ME, Zn induced proliferation of non-adherent as well as plastic adherent cells from either strain of mice. In cultures without 2-ME, Zn induced proliferation of thymocytes from Balb/c mice, whereas did not show constant mitogenic effect on thymocytes from C57BL/6 mice. In contrast, Zn determined higher levels of proliferation of thymocytes from either strain of mice when cultured with 2-ME. Zn had earlier and stronger mitogenic effect on mature thymocytes of either strain of mice than in total thymocytes, both in cultures with or without 2-ME. However, Zn did not induced proliferation in cultures of immature thymocytes of either strain of mice.

Animals↗
PubMed1976

Activation of purified human thymus-derived (T) cells by mitogens. II. Monocyte- macrophage potentiation of mitogen-induced DNA synthesis.

Thymus-derived (T) cells from peripheral blood were purified by rosette formation with neuraminidase-treated sheep red blood cells (SRBC) and centifugation on Ficoll-Hypaque. T cells recovered from the pellet were freed of SRBC by treatment with Tris-NH4Cl. T cells purified by this method showed a diminished ability to take up 3H-thymidine (3H-TdR) after mitogen stimulation when compared to the mitogenic response of an equal number of autologous peripheral blood mononuclear lymphocytes (PBL). Autologous monocytes restored the capacity of purified T cells to take up 3H-TdR in the presence of phytohemagglutinin (PHA) or Concanavalin A (Con A). The effect was proportional to the number of monocytes added. Similar restorative effects could be obtained with allogeneic or xenogeneic monocytes. These data suggest that the mitogenic stimulation of human PBL and Con A may reflect the participation of more than one cell type: the T cells and monocyte and that the genetic origin of the monocyte is not critical for augmentation of the mitogenic activation of human T cells.

Animals↗
PubMed1976

Extent of mitogen receptor occupancy and modulation of mitogen receptor exposure: possible mechanisms for the regulation of cell growth.

125I-Insulin was used as a model mitogen to examine the relationships of mitogen receptor occupancy and exposure in controlling cell replication. Labeled hormone was bound to substratum-attached, confluent fibroblasts with two affinities, K1 approximately equal to 2 X 108 M-1 and K2 approximately equal to 0.8 X 107 M-1. Approximately 9,000 receptors per cell were calculated from a scatchboard plot analysis with 80% of them of the affinity type. Treatment of confluent fibroblasts with 1.0 to 10 microng/ml of trypsin for 10 min increasd the number of exposed K2 sites by a factor of 2 to 3. Culturing the fibroblasts in the absence of serum for 12 to 24 hr also increased the quantity of exposed K2 sites to 60,000 per cell. The addition of unlabeled insulin to untreated, trypsin-treated, or serum-starved fibroblasts resulted in a stimulation of 2-deoxyglucose transport and thymidine incorporation activity that was proportional to the observed level of 125I-insulin binding. The quantity of exposed insulin receptors on uninfected fibroblasts decreases as the cell culture density increases. Hormone binding to B77 virus-transformed fibroblasts also decreases with culture density but plateaus at a density of 6 X 105 cells/plate. This resulted in a 2- to 3-fold difference in the level of exposed receptors between the uninfected and virus-transformed cells in confluent cultures, and proportionally higher rates of sugar transport and thymidine incorporation activity. Trypsin treatment and 12 hr of growth in the absence of serum did not result in an increase in the level of recepto exposure in the virus-transformed cells. The results of this study suggest that the pleotypic events associated with the stimulation of cell replication as represented by sugar transport and DNA synthesis are dependent upon and proportional to mitogen receptor occupancy. The control of cell replication, however, appears to be linked by a presently unknown mechanism with the degree of exposure of mitogen recipotrs. Receptor concentration is high and is similar in rapidly growing uninfected and virus-transformed cells, but the subsequent decrease observed with an increase in culture density reaches an early plateau for the transformed cells. This difference in exposed receptors could provide the growth advantage that is the hallmark of transformed cells.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1978

[Action of various mitogens (phytohemagglutinin, cocanavalin A, pokeweed mitogen) on a purified human B- and T-lymphocyte population mediating spontaneous rosette formation].

The activity of various most widely used "polyclonal" mitogens, such as PHA, Con A and PWM on human peripheral blood lymphocyte subpopulations, after separation into the two main functional classes (B and T), was investigated. For separating the lymphocyte subclasses, the E-rosette formation technique has been followed, using the gradient centrifuged pellet and supernatant respectively. For the mitogens' activity evaluation, micro-culture system has been performed and 3H thymidine uptake has been assessed. The PHA has been shown to be much more active on the T lymphocyte subclass, though the mitogen cannot be kept very selective. Very much higher activity on the T subclass shows the Con A, which could be considered selective, if we hypothesize an at least partial receptor competition at lymphocyte membrane level between the mitogen and sheep erythrocytes. The PWM has been found very little active and not specific for either lymphocyte subclass.

Adult↗
PubMed1996

Mitogen-activated protein kinase and mitogen-activated kinase phosphatase-1 expression in the Noble rat model of sex hormone-induced prostatic dysplasia and carcinoma.

Our recent studies have implicated the TGF-alpha/epidermal growth factor receptor pathway in the genesis of testosterone (T) and estradiol-17 beta (E2)-induced dysplasia in the dorsolateral prostate (DLP) of Noble rats. This pathway was also found to be markedly up-regulated in the androgen-independent transplantable carcinoma that arose from the DLP of a Noble rat. In the current study, we investigated the expression of mitogen-activated protein kinase (MAP-kinase) and mitogen-activated kinase phosphatase-1 (MKP-1), key downstream regulators of growth factor-activated signal transduction in the DLP of castrated, castrated T-supplemented, and T+E2-treated rats and in the androgen-independent transplantable carcinoma. Both MAP-kinase and MKP-1 expression in the DLP were found to be dependent on androgen stimulation. Immunoblots of DLP from T+E2 treated rats demonstrated a selective decline in MKP-1 levels with no alteration in MAP-kinase expression. These findings suggest that the dual hormone treatment induces changes in the signal transduction pathway, which favors the protracted mitogenic action of MAP-kinase. In situ hybridization and immunohistochemistry findings corroborated the immunoblot data but also revealed that both MAP-kinase and MKP-1 were strongly expressed in severely dysplastic lesions, which may indicate the presence of transformed cells in these foci. In this regard, both proteins were strongly expressed in samples of the androgen-independent transplantable carcinoma. Taken together, results from this and our recent study suggest that alterations in a growth factor-MAP-kinase pathway may be important events in the initiation and progression of prostatic carcinoma.

Animals↗