Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

During malignant transformation in skin, epidermal keratinocytes (KCs) frequently acquire the capacity to by-pass cellular senescence, a response that normally limits their unrestricted proliferation. Despite growing interest in the role for senescence during aging of skin and cutaneous carcinogenesis, little is known regarding regulation of three proteins encoded by the INK4a/ARF locus (p12, p14(ARF), p16) in KCs. In this study, several molecular pathways are explored using cultured KCs and KCs freshly isolated from psoriatic plaques. p16 and p14(ARF) are predominantly expressed spontaneously when foreskin-derived early-passage KCs undergo confluency-induced premature senescence. Induction of p14(ARF) on confluency occurred with low E2F-1 levels. Suspension of KCs in methylcellulose induced p12 expression. Addition of various cytokines (interferon-gamma, tumor necrosis factor-alpha) or a phorbol ester [12-O-tetradecanoylphorbol-13-acetate (TPA)] only induced p16, but not p14(ARF). Confluent KCs up-regulated Ras activity and the downstream signaling involving ERK. Addition of MAPK inhibitor blocked cytokine and TPA-induced p16 expression. Confluency and interferon-gamma induced premature senescence and p16 expression was linked to induction of the transcription factor Egr-1. KCs derived from chronic psoriatic plaques were characterized by enhanced p16, p14(ARF), and p12 expression accompanied by elevated Egr-1 levels. These results demonstrate that multiple and highly divergent stimuli can trigger the senescent checkpoint in human KCs with differential regulation of p16, p14(ARF), and p12. Although abnormal mitogenic signaling by oncogenic Ras is generally cited as being responsible for induction of premature senescence, our findings indicate that a broader perspective is warranted, to include confluency and cytokine-/TPA-induced pathways for KCs.
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PMID:Role of INK4a/Arf locus-encoded senescent checkpoints activated in normal and psoriatic keratinocytes. 1250 99

PKC, a major target for the tumor-promoting phorbol esters, has been implicated in the signal transduction pathways that mediate important functions in intestinal epithelial cells, including proliferation and carcinogenesis. With the use of IEC-18 cells arrested in G0/G1, addition of phorbol esters resulted in a modest increase in [3H]thymidine incorporation and a slight shift toward the S and G2/M phases of the cell cycle, whereas the combination of EGF and phorbol 12,13-dibutyrate (PDB) synergistically stimulated DNA synthesis. To investigate the effects of receptor-mediated PKC activation on mitogenesis, we demonstrated that ANG II induced ERK activation, a response completely blocked by pretreatment with mitogen/extracellular signal-regulated kinase inhibitors or specific PKC inhibitors. Furthermore, ANG II stimulated an over threefold increase in [3H]thymidine incorporation that was corroborated by flow cytometric analysis of the cell cycle to levels comparable to that achieved by the combination of EGF and PDB. Taken together, our results indicate that receptor-mediated PKC activation, as induced by ANG II, transduces mitogenic signals leading to DNA synthesis and cell proliferation in IEC-18 cells.
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PMID:ANG II stimulates PKC-dependent ERK activation, DNA synthesis, and cell division in intestinal epithelial cells. 1262 Aug 89

Dual specificity phosphatases (DSP) play an important role in control of the cell cycle and signal transduction. We have synthesized a new class of DSP inhibitors. Cpd 5 or [2-(2-mercaptoethanol)-3-methyl-1,4-naphthoquinone] is one of the most potent of these. It inhibits DSPs of cells in culture and induces tyrosine phosphorylation of various DSP substrates, including the Cdc25 target Cdks and it potently inhibits cell growth. In this study, we have evaluated Cpd 5 in vivo for its antitumor and growth inhibitory activity on carcinogen-altered foci. Cpd 5 inhibited growth of the transplantable rat hepatoma cell line JM-1 in vitro, with concomitant phosphorylation of the mitogen-activated protein kinase ERK1/2 but not JNK1/2 or p38. This ERK phosphorylation was associated with growth inhibition, as the ERK phosphorylation inhibitor PD098059 antagonized both ERK phosphorylation and growth inhibition. JM-1 cell lysates were found to contain ERK1/2-specific phosphatase(s) that could be inhibited by Cpd 5 and which are thought to be its major targets. Cpd 5 caused significant inhibition of both intrahepatic and subcutaneous (s.c.) growth of transplanted JM-1 cells in male Fischer F344 rats. The treatment was equally effective whether Cpd 5 was administered either as a single, acute dose or chronically as several lower doses. However, toxicity was much lower with chronic treatment. As in JM-1 cells in vitro, ERK1/2 was phosphorylated when rats in vivo were treated with Cpd 5 and tumor growth inhibition in vivo also was antagonized by treating rats with the ERK1/2 phosphorylation inhibitor PD098059. A single dose of Cpd 5 also inhibited the formation of glutathione S-transferase-pi enzyme-altered cells induced by the hepatocarcinogen N-nitrosodiethylamine. This is the first report of the in vivo activity and growth inhibitory mechanism of a novel class of K vitamin growth inhibitors that have potent tyrosine phosphatase activity.
Carcinogenesis 2003 Mar
PMID:Antitumor and anticarcinogenic actions of Cpd 5: a new class of protein phosphatase inhibitor. 1266 99

The induction of glutathione S-transferases by flavonoids is associated with cancer chemopreventive effects. We reported that 2'-amino-3'-methoxyflavone (PD98059), an MKK1 inhibitor, induces glutathione S-transferase A2 (rGSTA2). This report comparatively examines the role of CCAAT/enhancer-binding protein (C/EBP) and Nrf2 in the induction of rGSTA2 by PD98059. We first assessed whether the MKK1/ERK1/2 pathway regulated rGSTA2 induction. Northern and western blot analyses showed that PD98059 at the concentrations effective for the inhibition of MKK1 increased the rGSTA2 protein and mRNA levels in H4IIE cells. PD98059 also induced rGSTA2 in cells stably transfected with dominant-negative mutant of MKK1(-), which provided evidence that the inhibition of MKK1/ERK1/2 by PD98059 was not responsible for rGSTA2 induction. Gel shift assay and immunoblot analysis of subcellular fractions revealed that PD98059 caused nuclear translocation of C/EBP beta and increased C/EBP DNA binding, which was super-shifted with anti-C/EBP beta antibody. Nrf2 was not activated by PD98059. PD98059 increased the luciferase reporter gene activity in cells transfected with the C/EBP-containing -1.65 kb flanking region of the rGSTA2 gene. Deletion of the C/EBP-binding site or over-expression of dominant-negative mutant of C/EBP abolished the reporter gene activity. Flavone, a backbone structure of PD98059, also induced nuclear translocation of C/EBP beta and C/EBP-mediated rGSTA2 gene induction. Inhibition of phosphatidylinositol 3-kinase abolished C/EBP beta-mediated rGSTA2 induction by PD98059. These results provide evidence that PD98059 and flavone induce nuclear translocation of C/EBP beta and activate the C/EBP-binding site in the rGSTA2 gene, which constitutes the distinct pathway for the enzyme induction irrespective of the inhibition of MKK1/ERK activity.
Carcinogenesis 2003 Mar
PMID:Activation of CCAAT/enhancer-binding protein beta by 2'-amino-3'-methoxyflavone (PD98059) leads to the induction of glutathione S-transferase A2. 1266 7

The cytokine transforming growth factor beta (TGF-beta) plays an important role in preventing tumor formation by blocking cell cycle progression. Accordingly, many cancers demonstrate mutations in TGF-beta signaling components or enhanced expression of inhibitors of the TGF-beta pathway such as Smad7. In this report we show that the oncoprotein HER2/Neu is able to collaborate with the ETS transcription factor ER81 to activate Smad7 transcription in breast, endometrial, and ovarian cancer cell lines. ER81 binds to two ETS sites within the Smad7 promoter, and mutation of one of these ETS sites greatly decreases Smad7 induction by HER2/Neu and ER81. Furthermore, we show that Smad7 activation involves the processing of signals from HER2/Neu to ER81 via the ERK mitogen-activated protein kinase pathway. Thus, we have uncovered a novel mechanism by which oncogenic HER2/Neu, in collaboration with ER81, can induce carcinogenesis through Smad7 up-regulation. Moreover, we show that TAK1, a TGF-beta-activated protein kinase, stimulates ER81 via the p38 mitogen-activated protein kinase pathway and thereby induces the Smad7 promoter. This suggests that attenuation of TGF-beta signaling by activating Smad7 transcription may proceed not only through TGF-beta receptor-regulated Smad proteins but also through an independent pathway involving ER81 and TAK1.
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PMID:HER2/Neu- and TAK1-mediated up-regulation of the transforming growth factor beta inhibitor Smad7 via the ETS protein ER81. 1294 87

Characterization of intracellular signaling pathways should lead to a better understanding of ovarian epithelial carcinogenesis and provide an opportunity to interfere with signal transduction targets involved in ovarian tumor cell growth, survival, and progression. Challenges toward such an effort are significant because many of these signals are part of cascades within an intricate and likely redundant intracellular signaling network (Fig.1). For instance, a given signal may activate a dual intracellular pathway (ie, MEK1-MAPK and PI3K/Akt required for fibronectin-dependent activation of matrix metalloproteinase 9). A single pathway also may transduce more than one biologic or oncogenic signal (ie, PI3K signaling in epithelial and endothelial cell growth and sprouting of neovessels). Despite these challenges, evidence for therapeutic targeting of signal transduction pathways is accumulating in human cancer. For instance, the EGF-specific tyrosine kinase inhibitor ZD 1839 (Iressa) may have a beneficial therapeutic effect on ovarian epithelial cancer. Therapy of this cancer may include inhibitors of PI kinase (quercetin), ezrin and PIP kinase (genistein). The G protein-coupled family of receptors, including LPA, also is an attractive target to drugs, although their frequent pleiotropic functions may be at times toxic and lack specificity. Because of the lack of notable toxicity, PI3K/Akt pathway inhibitors such as FTIs are a promising targeted therapy of ovarian epithelial cancer. Increasing insight into the oncogenic pathways involved in ovarian epithelial cancer also is helping clinicians to understand better the phenomenon of chemoresistance in this malignancy. Oncogenic activation of gamma-synuclein promotes cell survival and provides resistance to paclitaxel, but such a resistance is partially overcome by an MEK inhibitor that suppresses ERK activity. Ovarian epithelial cancer is a complex group of neoplasms with an overall poor prognosis. Comprehension of this cancer pathobiology suffers because of an incomplete understanding of precursor lesions and the absence of an orthotopic animal model until very recently. It can be predicted with confidence, however, that the discovery of potent inhibitors of signal transduction and the development of discovery tools, such as proteomics and metabolomics, may change the way by which clinicians may now address basic biomedical questions in this insidious and lethal disease.
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PMID:Oncogenic pathways implicated in ovarian epithelial cancer. 1295 83

Organochlorine compounds have been demonstrated to have detrimental health effects in both wildlife and humans, an effect largely attributed to their ability to mimic the hormone estrogen. Our laboratory has studied cell signaling by environmental chemicals associated with the estrogen receptor (ER) and more recently via ER-independent mechanisms. Here, we show that the organochlorine pesticide dichlorodiphenyltrichloroethane (DDT) and its metabolites induce a stress mitogen-activated protein kinase (MAPK) that leads to AP-1 activation. Through the use of a dominant negative c-Fos mutant, we show that DDT exposure induces the collagenase promoter in an AP-1-dependent manner. DDT stimulates an AP-1 complex shift at the DNA to one favoring c-Jun/c-Fos dimers through both increasing c-Jun levels and by post-translational activation of c-Jun and c-Fos in HEK 293 and human endometrial Ishikawa cells. DDT treatment induces phosphorylation of ERK and p38, while JNK phosphorylation levels are slightly decreased. Using pharmacological and molecular inhibitors of the various MAPKs, we implicate the p38 signaling cascade, and to a lesser extent ERK, as necessary pathways for AP-1-mediated gene expression induction by organochlorines. Taken together, these results demonstrate that organochlorines induce the collagenase promoter via sequential activation of the p38 kinase cascade and AP-1.
Carcinogenesis 2004 Feb
PMID:Mechanism of AP-1-mediated gene expression by select organochlorines through the p38 MAPK pathway. 1460 93

Integrin-mediated signalling has been implicated in asbestos-induced carcinogenesis. In studies here, we examined signal transduction events associated with integrin-directed cell reactions triggered by crocidolite asbestos in the pleural mesothelial cell line 4/4 RM-4. Crocidolite fibres induced a significant time- and dose-dependent activation of the extracellular-signal-regulated kinases ERK1 and ERK2. ERK activation was specifically inhibited by integrin-blocking agents, that are integrin-binding peptides containing the sequence arginine-glycine-aspartic acid (RGD), and monoclonal antibodies against the integrin beta1-chain. Integrin-dependent activation of ERK1/2 in response to asbestos appeared to be independent of focal adhesion kinase pp125FAK (FAK) since FAK autophosphorylation remained unaffected in crocidolite-exposed mesothelial cells. Instead, we observed striking similarities in the kinetics of asbestos-induced ERK1/2 responses and phosphorylation of protein kinase B (AKT) at serine 473, a possible target residue for integrin-linked kinase. As with ERK activation, asbestos-induced AKT stimulation was significantly blocked by both the RGD-peptide and the beta1-integrin antibodies. These studies are the first to establish that in mesothelial cells ERK1/2 and AKT are simultaneously phosphorylated upon asbestos exposure in a beta1-integrin-dependent manner.
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PMID:beta1-integrin mediates asbestos-induced phosphorylation of AKT and ERK1/2 in a rat pleural mesothelial cell line. 1462 93

Ovarian steroids are important modulators of normal cell growth and differentiation as well as of carcinogenesis. External stimuli trigger cell surface receptors, resulting in activation of central signal transduction pathways, that are mediated by members of the mitogen-activated protein kinase (MAPK) family. These in turn, indirectly regulate cellular functions such as cell proliferation, cell cycle, and maintenance of malignant phenotype. In our in vitro study, we have investigated the effects of two synthetic estrogens on ERK 2 activation. Estrogen receptor positive cells were incubated with the synthetic estrogens, ethinylestradiol (10(-9) mol/l) and 17 beta-estradiol valerate (10(-9) mol/l), epidermal growth factor (EGF) (10 ng/ml) and the natural estrogen 17 beta-estradiol (10(-9) mol/l), for 5 min. The same experiments were repeated prior to preincubation with the antiestrogen ICI 182780. ERK 2 or the active form alone were detected by immunoblotting. A cell proliferation assay was used to study the response of cells to various treatments. Time kinetics were performed to study duration of kinase activated state. Cell incubation with EGF as well as with either natural or synthetic estrogen stimulated proliferation. ICI 182780 inhibited this effect, but only in the case of estrogen. Synthetic estrogens activated MAP kinase in a time-dependent fashion, similar to 17 beta-estradiol. The estrogen receptor antagonist ICI 182780 blocked this effect. EGF induced a more pronounced and prolonged activation, even in the presence of the antiestrogen. Ethinylestradiol as used in oral contraceptives, and 17 beta-estradiol and 17 beta-estradiol valerate as used in hormone replacement therapy, are able to activate MAP kinase. This activation was blocked by an antiestrogen.
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PMID:Synthetic estrogen-mediated activation of ERK 2 intracellular signaling molecule. 1471 May 92

The chemopreventive properties of the isothiocyanates have been attributed to their ability to inhibit phase I enzymes that activate procarcinogens, induce phase II protective enzymes and trigger apoptosis in transformed cells. In this study we provide evidence for a new mechanism of chemoprevention, wherein sublethal doses of phenethyl isothiocyanate (PEITC) sensitize cells to Fas-mediated apoptosis. The phenomenon was observed in the Fas-resistant T24 bladder carcinoma cell line and in Jurkat T cells overexpressing the anti-apoptotic protein Bcl-2. Caspase-3-like activity was increased up to 20-fold of that observed with either PEITC or anti-Fas antibody alone. While PEITC activated ERK, JNK and p38, inhibitors of these MAP kinases did not block apoptosis. PEITC transiently depleted cellular glutathione, providing a putative mechanism for sensitizing the cells to apoptosis. However, lowering glutathione with buthionine sulfoximine did not mimic the effect of PEITC. Instead, we propose that PEITC promotes apoptosis by directly modifying intracellular thiol proteins. The ability of PEITC to sensitize cells to receptor-mediated apoptosis provides an additional mechanism to explain its chemopreventive properties.
Carcinogenesis 2004 May
PMID:The chemopreventive agent phenethyl isothiocyanate sensitizes cells to Fas-mediated apoptosis. 1472 92


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