Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P51812 (mitogen-activated protein)
 10,636 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Exposure of mammalian cells to solar ultraviolet (UV) radiation leads to the expression of several genes, and UV has been recognized as a major initiator and promoter of skin cancer. The component of the solar radiation that contributes most to human skin malignancy is UVB (280-320 nm) and, to a lesser extent, UVA (320-400 nm), whereas the high-energy UVC (100-280 nm) is absorbed by the earth's upper atmosphere. Sublethal doses of UVB produce strong induction of c-jun and c-fos transcripts in several cells including human primary keratinocytes. The present report confirms that this is also the case in the HaCaT cell line and shows that similar UVB doses are potent inducers of the JNK/SAPK family of mitogen-activated protein kinases but only weak activators of ERKs. Epidermal growth factor (EGF) caused rapid induction of both JNK- and ERK-signaling pathways, and the downmodulation of the EGF-signaling pathway by EGF pre-treatment inhibited the UVB-induced JNK1 activation. Prior UVB irradiation of the cells decreased the level of the ERK2 activation by a subsequent EGF treatment, but this sensitized the cells and allowed for the super-activation of JNK1 after a rechallenge with either UVB or EGF. The antioxidant N-acetylcysteine impaired the UVB- and EGF-induced activation of JNK1. Our data suggest the presence of shared signaling component(s) in the UVB- and EGF-induced cellular response pathways and imply that oxidative stress plays a significant role in the activation of JNK1 by UVB and EGF.
 ...
PMID:Differential stimulation of ERK and JNK activities by ultraviolet B irradiation and epidermal growth factor in human keratinocytes. 918 16

We demonstrate herein the ability of transforming growth factor-beta-2 (TGFbeta2) to potently activate extracellular signal-regulated kinase 2 (ERK2) in the highly TGFbeta-sensitive breast cancer cell (BCC) line Hs578T. The ERK2 isoform was activated by 3-fold within 5 min of TGFbeta2 addition to Hs578T cells. However, TGFbeta2 only slightly activated ERK2 (1.5-fold) in the partially TGFbeta-responsive BCC line MDA-MB-23 1. The magnitude of the difference in activation of ERK2 by TGFbeta2 in the two cell lines paralleled the difference in the IC50 values for TGFbeta inhibition of DNA synthesis; the IC50 value in the MDA-MB-231 cells was 32-fold greater than that in the Hs578T cells. Further, our data demonstrate that TGFbeta2 activated the stress-activated protein kinase/Jun N-terminal kinase (SAPK/JNK) type of mitogen-activated protein kinases (MAPKs); maximal induction levels were 2.5-fold above basal values and were attained at 30 min after TGFbeta2 treatment. Transient co-transfection of a luciferase reporter construct (3TP-Lux) containing three AP-1 sites and the plasminogen activator inhibitor-1 (PAI-1) promoter, in conjunction with a construct that directs expression of a dominant-negative mutant ERK2 (TAYF) protein, did not block the ability of TGFbeta to induce AP-1 or PAI-1 activity. In contrast, TAYF ERK2 was able to block EGF and insulin-induced 3TP-Lux-reporter activity. These results indicate that in these BCCs, the activation of ERK2 by TGFbeta is more tightly linked to the ability of TGFbeta to inhibit DNA synthesis than to the ability to stimulate promoter regions important for TGFbeta production and control of the extracellular matrix. In addition, this is the first demonstration that TGFbeta can activate the SAPK/JNK type of MAPK in TGFbeta-sensitive human BCCs.
Cancer Lett 1997 Jul 15
PMID:TGFbeta regulation of mitogen-activated protein kinases in human breast cancer cells. 923 30

Thapsigargin is a non-phorbol ester-type tumor promoter that elevates the intracellular Ca2+ (Ca(i)2+) levels by blocking the microsomal Ca2+ ATPase. At present, the consequence of this Ca(i)2+ increase and the nature of the tumorigenicity of thapsigargin still remain to be elucidated. Previously, we demonstrated that thapsigargin activates the mitogen-activated protein (MAP) kinase via Ca(i)2+ but independently of protein kinase C or Ca2+ influx. Here, we show that thapsigargin also rapidly stimulates the Src tyrosine kinase. Transfection of a v-Src gene into a hippocampal cell line (H19-7) renders a constitutive activation of MAP kinase, whereas transfection of a kinase-deficient Src mutant blocks the activation by thapsigargin, suggesting that Src is required for the thapsigargin-induced MAP kinase activation. Cotransfection of a dominant-inhibitory Raf-1 and the v-Src genes into H19-7 cells results in an inhibition of the otherwise constitutively elevated MAP kinase activity, suggesting that Raf-1 is required for the Src-dependent activation of MAP kinase. Similarly, in the LA-90 cells, expression of a temperature-sensitive allele of v-Src constitutively activates Raf-1 and MAP kinase, whereas expression of a dominant-inhibitory Raf-1 mutant abolishes the MAP kinase activation induced by either v-Src or thapsigargin treatment. Together, these results suggest that thapsigargin stimulates MAP kinase signaling via Src and Raf-1. The activation of this Src-MAP kinase pathway suggests a biochemical mechanism for the tumorigenic nature of thapsigargin.
Cancer Res 1997 Aug 01
PMID:Src tyrosine kinase mediates stimulation of Raf-1 and mitogen-activated protein kinase by the tumor promoter thapsigargin. 924 45

The antioxidant N-acetyl-L-cysteine (NAC) has been increasingly used as an experimental tool to assess involvement of reactive oxygen species in cell signaling and is being evaluated as a preventive and therapeutic agent for cancer and pulmonary diseases related to inflammation and oxidative stress. However, a detailed characterization of the effect of NAC on cell cycle progression has not been reported. In the present study, modulation of cell cycle progression by NAC was analyzed in mouse fibroblast NIH3T3 cells grown in 10% fetal bovine serum. Complete inhibition of NIH3T3 cell proliferation was obtained with 20 mM NAC. Inhibition of cell proliferation by NAC (at or below 20 mM) was not due to cell death, and the antiproliferative effect of NAC was reversible. Flow cytometric analysis of cell cycle phase distribution indicated that NAC blocked the cell cycle in the G1 phase. Consistent with this observation, NAC inhibited DNA synthesis. After releasing the G1-block by NAC, S phase re-entry occurred between 8 and 12 h, suggesting that NAC blocked the cell cycle in early to mid-G1 phase. NAC prevented activation of mitogen-activated protein (MAP) kinases p42MAPK and p44MAPK and inhibited expression of cyclin D1, but had no effect on the levels of proliferating cell nuclear antigen. Incubation of cells with PD98059, a specific inhibitor of MAP kinase kinase 1, partially arrested the cell cycle in the G1 phase. These results indicate that the antiproliferative effect of NAC is linked in part to inhibition of the MAP kinase pathway.
 ...
PMID:Suppression of fibroblast cell cycle progression in G1 phase by N-acetylcysteine. 957 90

The molecular genetic events involved in the etiology of human granulosa cell (GC) tumors, which represent approximately 7% of all malignant ovarian neoplasms, are unknown. Amplification and/or overexpression of the ERBB genes are a feature of many cancer types, and overexpression of erbB2 correlates with poor prognosis in epithelial ovarian cancer. In the present study, we used immunohistochemistry to determine the level and frequency of expression of different erbB receptors in GC tumors. Ten of 12 tumors expressed erbB4 at moderate to high levels in >50% of cancer cells, whereas erbB2 (6 of 12) and erbB3 (2 of 12) were expressed less frequently. Western blot experiments showed that the only available GC tumor cell line, COV434, also expressed erbB receptors. Heregulin (HRG)-beta2, a ligand for erbB3 and erbB4 receptors, stimulated tyrosine phosphorylation of the erbB receptors, which was accompanied by activation of Erk1 and Erk2, two mitogen-activated protein kinases with a functional role in mitogenesis. Importantly, HRG increased cell proliferation in COV434 cells, and treatment with HRG/PE40, a ligand toxin shown previously to be cytotoxic against human breast cancer cells overexpressing erbB receptors, led to a dramatic and irreversible decrease in cell number. These results indicate that erbB receptor signaling pathways may be critical in the control of GC tumor cell proliferation and that HRG/PE40 is a potential therapeutic agent for the treatment of GC tumors.
Cancer Res 1998 May 01
PMID:Granulosa cell tumors express erbB4 and are sensitive to the cytotoxic action of heregulin-beta2/PE40. 958 10

Although nicotine has been implicated as a potential factor in the pathogenesis of human lung cancer, its mechanism of action in the development of this cancer remains largely unknown. The present study provides evidence that nicotine (a) activates the mitogen-activated protein (MAP) kinase signalling pathway in lung cancer cells, specifically extracellular signal-regulated kinase (ERK2), resulting in increased expression of the bcl-2 protein and inhibition of apoptosis in these cells; and (b) blocks the inhibition of protein kinase C (PKC) and ERK2 activity in lung cancer cells by anti-cancer agents, such as therapeutic opioid drugs, and thus can adversely affect cancer therapy. Nicotine appears to have no effect on the activities of c-jun NH2-terminal protein kinase (JNK) and p38 MAP kinases, which have also been shown to be involved in apoptosis. While exposure to nicotine can result in the activation of the two major signalling pathways (MAP kinase and PKC) that are known to inhibit apoptosis, nicotine regulation of MAP (ERK2) kinase activity is not dependent on PKC. These effects of nicotine occur at concentrations of 1 microM or less, that are generally found in the blood of smokers, and could lead to disruption of the critical balance between cell death and proliferation, resulting in the unregulated growth of cells. The findings suggest caution in the use of smokeless tobacco products to treat smoking addiction, as they could have a potentially deleterious effect in patients with undetectable early tumour development.
 ...
PMID:Signalling pathways involved in nicotine regulation of apoptosis of human lung cancer cells. 960 Mar 37

The activation status of the ras pathway was studied in eight ovarian tumor cell lines. Three biochemical parameters indicative of ras activation were tested: (a) the ratio of the ras-GTP:ras-GDP complex; (b) the activity of mitogen-activated protein kinases p42/p44; and (c) ets-2 phosphorylation at position threonine 72, a mitogen-activated protein kinase phosphorylation site in vivo. Four of the ovarian tumor cell lines had an activated ras pathway by these three parameters, whereas only one of these contained a mutated ras gene. In addition, ras/ets-2 responsive genes such as the urokinase plasminogen activator (uPA) were activated in these four cell lines. Transient transfection assays indicated that the compound ets-AP1 oncogene responsive enhancer present in the uPA gene was the target of ras signaling in ovarian tumor cells and that the combination of activated ras and ets-2 could superactivate the uPA enhancer element. Coexpression of the dominant-negative ras-Asn17 cDNA gene abrogated activity of this uPA element in ovarian tumor cells. These data indicate that ets-2 is a nuclear target of ras action in ovarian tumor cell lines and that ras signaling pathways may be activated in ovarian cancer by mechanisms independent of direct genetic damage to ras genes.
Cancer Res 1998 May 15
PMID:Activation of the ras-mitogen-activated protein kinase pathway and phosphorylation of ets-2 at position threonine 72 in human ovarian cancer cell lines. 960 74

UV irradiation leads to severe damage, such as cutaneous inflammation, immunosuppression, and cancer, but it also results in a gene induction protective response termed the UV response. The signal triggering the UV response was thought to originate from DNA damage; recent findings, however, have shown that it is initiated at or near the cell membrane and transmitted via cytoplasmic kinase cascades to induce gene transcription. Urokinase-type plasminogen activator (uPA) was the first protein shown to be UV inducible in xeroderma pigmentosum DNA repair-deficient human cells. However, the underlying molecular mechanisms responsible for the induction were not elucidated. We have found that the endogenous murine uPA gene product is transcriptionally upregulated by UV in NIH 3T3 fibroblast and F9 teratocarcinoma cells. This induction required an activator protein 1 (AP1) enhancer element located at -2.4 kb, since deletion of this site abrogated the induction. We analyzed the contribution of the three different types of UV-inducible mitogen-activated protein (MAP) kinases (ERK, JNK/SAPK, and p38) to the activation of the murine uPA promoter by UV. MEKK1, a specific JNK activator, induced transcription from the uPA promoter in the absence of UV treatment, whereas coexpression of catalytically inactive MEKK1(K432M) and of cytoplasmic JNK inhibitor JIP-1 inhibited UV-induced uPA transcriptional activity. In contrast, neither dominant negative MKK6 (or SB203580) nor PD98059, which specifically inhibit p38 and ERK MAP kinase pathways, respectively, could abrogate the UV-induced effect. Moreover, our results indicated that wild-type N-terminal c-Jun, but not mutated c-Jun (Ala-63/73), was able to mediate UV-induced uPA transcriptional activity. Taken together, we show for the first time that kinases of the JNK family can activate the uPA promoter. This activation links external UV stimulation and AP1-dependent uPA transcription, providing a transcription-coupled signal transduction pathway for the induction of the murine uPA gene by UV.
 ...
PMID:UV irradiation induces the murine urokinase-type plasminogen activator gene via the c-Jun N-terminal kinase signaling pathway: requirement of an AP1 enhancer element. 967 63

Protein kinases of the Raf family act as signal-transducing elements downstream of activated cell surface receptors and are involved in the regulation of proliferation, differentiation, and cell survival. Whereas the role of c-Raf-1 as a mitogen-activated protein/extracellular signal-regulated kinase activator within the mitogenic cascade is well established, less is known about the mammalian Raf isoforms A-Raf and B-Raf. Here we report that B-Raf binds to PA28alpha, one of two subunits of the 11S regulator of proteasomes. PA28alpha was isolated as a B-Raf-binding protein in a yeast two-hybrid screen of a PC12 cDNA library. Both proteins can be coimmunoprecipitated after transient expression in 293 cells. No association could be found between PA28alpha and A-Raf or c-Raf-1. B-Raf binds to a region in PA28alpha that is important for its proteasome-activating function.
Cancer Res 1998 Jul 15
PMID:Interaction between the protein kinase B-Raf and the alpha-subunit of the 11S proteasome regulator. 967 60

Retinoic acid (RA) activated the extracellular signal-regulated kinase (ERK) 2 mitogen-activated protein kinase (MAPK) of HL-60 human myeloblastic leukemia cells before causing myeloid differentiation and cell cycle arrest associated with hypophosphorylation of the retinoblastoma (RB) tumor suppressor protein. ERK2 activation by mitogen-activated protein/ERK kinase (MEK) was necessary for RA-induced differentiation in studies using PD98059 to block MEK phosphorylation. G0 growth arrest and RB tumor suppressor protein hypophosphorylation (which is typically associated with induced differentiation and G0 arrest), two putatively RB-regulated processes, also depended on ERK2 activation by MEK. Activation of ERK2 by RA occurred within hours and persisted until the onset of RB hypophosphorylation, differentiation, and arrest. ERK2 activation was probably needed early, because delaying the addition of PD98059 relative to that of RA restored most of the RA-induced cellular response. In contrast to RA (which activates RA receptors (RARs) and retinoid X receptors in HL-60 cells with its metabolite retinoids), a retinoid that selectively binds RAR-gamma, which is not expressed in HL-60 cells, was relatively ineffective in causing ERK2 activation. This is consistent with the need for a nuclear retinoid receptor function in RA-induced ERK2 activation. RA reduced the amount of unphosphorylated RAR-alpha, whose activation is necessary for RA-induced differentiation and arrest. This shifted the ratio of phosphorylated:unphosphorylated RAR-alpha to predominantly the phosphorylated form. Unlike other steroid thyroid hormone receptors susceptible to phosphorylation and activation by MAPKs, RAR-alpha was not phosphorylated by the activated ERK2 MAPK. The results thus show that RA augments MEK-dependent ERK2 activation that is needed for subsequent RB hypophosphorylation, cell differentiation, and G0 arrest. The process seems to be nuclear receptor dependent and an early seminal component of RA signaling causing differentiation and growth arrest.
Cancer Res 1998 Jul 15
PMID:Retinoic acid induced mitogen-activated protein (MAP)/extracellular signal-regulated kinase (ERK) kinase-dependent MAP kinase activation needed to elicit HL-60 cell differentiation and growth arrest. 967 85


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>