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)

Medaka fish are an established non-mammalian research model for the study of liver carcinogenesis and exposure to environmental pollutants. Studies have emphasized the development of hepatic neoplasms in medaka following exposure to model carcinogens. To date however, little information is known regarding the mechanisms underlying initiation of hepatic tumors in this species. The aim of this study was to relate our understanding of diethylnitrosamine (DEN)-induced tumor formation to ras gene activation in hepatic neoplasms of exposed medaka. Initial studies were conducted to identify medaka ras exons 1 and 2 by reverse transcriptase polymerase chain reaction (RT-PCR). Amplification of ras exons 1 and 2 from untreated medaka liver resulted in the identification of three polymorphic ras sequence variants exhibiting a high degree of homology to other teleost and mammalian ras genes. Exposure of medaka to 159 ppm of DEN resulted in a wide range of hepatic neoplasms including: hepatocellular adenomas, hepatocellular carcinomas, cholangiomas, and mixed hepatocholangiocellular carcinomas. Individual liver tumors were examined for oncogenically activating ras mutations by probing genomic DNA with probes specific for activating point mutations or by direct cloning and sequencing of ras transcripts using RT-PCR. Using allele-specific oligonucleotide (ASO) analysis, a single point mutation was detected in codon 12 position two in 8/25 (32%) tumors examined. Mutated ras alleles were additionally detected in 12 of 39 (30%) medaka liver tumors by sequence analysis. Ten of the 12 mutations identified contained a single point mutation at codon 12 resulting in a Gly to Asp amino acid substitution. Two unique mutations were identified at codon 16 resulting in either Lys to Asn or Lys to Thr amino acid substitutions. Our results show that ras mutations are induced by DEN and are present in over 30% of the fish that developed tumors. A ras mutation incidence of 30% is similar to that reported in mammalian species exposed to DEN. While mutations at codon 12 have previously been reported, the present study is the first in vivo report of ras point mutations at codon 16.
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PMID:ras oncogene mutations in diethylnitrosamine-induced hepatic tumors in medaka (Oryzias latipes), a teleost fish. 1294 13

Protein kinase C (PKC) is a family of serine/threonine kinases that is involved in the transduction of signals for cell proliferation and differentiation. The important role of PKC in processes relevant to neoplastic transformation, carcinogenesis and tumour cell invasion renders it a potentially suitable target for anticancer therapy. Furthermore, there is accumulating evidence that selective targeting of PKC may improve the therapeutic efficacy of established neoplastic agents and sensitise cells to ionising radiation. This article reviews the rationale for targeting PKC, focuses on its role in breast cancer and reviews the preclinical and clinical data available for the efficacy of PKC inhibition.
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PMID:Protein kinase C: a target for anticancer drugs? 1516 95

The mouse parathyroid hormone-like hormone Pthlh(Pro) and Pthlh(Thr) variants are linked with susceptibility and resistance to skin carcinogenesis of Car-S and Car-R mice, respectively, and with in vitro effects (Oncogene, 19: 5324-5328, 2000). We have identified an additional Pthlh variant, consisting of Thr and three amino-acid changes in the C-terminus (Pthlh(SerAspTyr)), carried by an evolutionarily distant Mus spretus (SPRET/Ei) inbred strain. When transfected into NCI-H520 tumor cells, this Pthlh(SerAspTyr) variant did not stimulate tumor growth in nude mice. Analysis of cell adhesion, migration, and invasion patterns of Pthlh(Pro)-, Pthlh(Thr)-, and Pthlh(SerAspTyr)-transfected NCI-H520 cells revealed a 1.5-fold decrease in adhesion efficiency on both collagen type I and Matrigel, and a 5-6-fold increase in migration capability in Pthlh(Pro) transfectants as compared to nontransfected, vector-transfected, Pthlh(Thr)-, or Pthlh(SerAspTyr)-transfected cells. These findings suggest that the cancer modifier effects of the mouse Pthlh gene are mediated by differential cell adhesion and migration effects of PTHrP variants.
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PMID:Allele-specific patterns of the mouse parathyroid hormone-related protein: influences on cell adhesion and migration. 1458 97

Aberrant Wnt/beta-catenin signaling caused by mutations in exon 3 of the beta-catenin gene has been identified in a number of human malignancies, including stomach cancer. However, studies of mutation frequency have yielded conflicting results, and timing during progression remains largely unknown. In this study, we utilized an animal model to address this question. A total of 20 ACI male rats were treated with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) in the drinking water and 22 induced differentiated adenocarcinomas were histopathologically and immunohistochemically evaluated for beta-catenin localization. Fourteen tumors (63.6%) that showed homogeneous low-grade morphology, preserving cell polarity, were found to harbor beta-catenin protein on the cell membranes (M). Eight tumors exhibited regions of high-grade morphology among areas with low-grade morphology, and they were characterized by denser cell growth and loss of cell polarity. Among these 8 tumors, 4 (18.2%) showed cytoplasmic localization (C) of beta-catenin in small regions. The remaining 4 tumors (18.2%) contained more dysplastic regions that displayed nuclear (N) beta-catenin staining. Analysis of DNA obtained by microdissection demonstrated that all of 4 regions with C staining and 20 with M staining, as well as 17 samples of surrounding normal mucosa (S) had wild-type beta-catenin. In contrast, all of 3 regions with N staining featured mutations (3 of 3 = 100%; N vs. C, P < 0.05; N vs. M and N vs. S, P < 0.001, Fisher's exact test) in exon 3, at glycine 34, threonine 41, and serine 45, which affected phosphorylation sites. In conclusion, beta-catenin mutations appear to be associated with the late progression stage of adenocarcinoma development in rat stomach carcinogenesis, in contrast to the case of colorectal cancers, in which mutations appear to occur in the early stages.
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PMID:beta-Catenin mutations and nuclear accumulation during progression of rat stomach adenocarcinomas. 1466 19

The hepatitis C virus (HCV) core protein has been implicated in the transregulation of various RNA polymerase (Pol) II dependent genes as well as in the control of cellular growth and proliferation. In this study, we show that the core protein, whether individually expressed or produced as part of the HCV viral polyprotein, is the only viral product that has the potential to activate RNA Pol I transcription. Deletion analysis demonstrated that the fragment containing the N-terminal 1-156 residues, but not the 1-122 residues, of HCV core protein confers the same level of transactivation activity as the full-length protein. Moreover, the integrity of the Ser(116) and Arg(117) residues of HCV core protein was found to be critical for its transregulatory functions. We used DNA affinity chromatography to analyze the human ribosomal RNA promoter associated transcription machinery, and the results indicated that recruitment of the upstream binding factor and RNA Pol I to the ribosomal RNA promoter is enhanced in the presence of HCV core protein. Additionally, the HCV core protein mediated activation of ribosomal RNA transcription is accompanied by the hyperphosphorylation of upstream binding factor on serine residues, but not on threonine residues. Moreover, HCV core protein is present within the RNA Pol I multiprotein complex, indicating its direct involvement in facilitating the formation of a functional transcription complex. Protein-protein interaction studies further indicated that HCV core protein can associate with the selectivity factor (SL1) via direct contact with a specific component, TATA-binding protein (TBP). Additionally, the HCV core protein in cooperation with TBP is able to activate RNA Pol II and Pol III mediated transcription, in addition to RNA Pol I transcription. Thus, the results of this study suggest that HCV has evolved a mechanism to deregulate all three nuclear transcription systems, partly through targeting of the common transcription factor, TBP. Notably, the ability of the HCV core protein to upregulate RNA Pol I and Pol III transcription supports its active role in promoting cell growth, proliferation, and the progression of liver carcinogenesis during HCV infection.
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PMID:Activation of RNA polymerase I transcription by hepatitis C virus core protein. 1473 Feb 12

Chemoprevention has become an effective cancer control modality; however, the search for novel agent(s) for the armamentarium of cancer chemoprevention continues. We argue that agents capable for inhibition of promotion stage of tumorigenesis with the ability to intervene at several critical pathways in the tumorigenesis process will have greater advantage over other single-target agents. Lupeol, a triterpene, is the principal constituent of common fruit plants such as olive, mango, fig and medicinal herbs that have been used to treat skin aliments. Lupeol has been reported to possess a wide range of medicinal properties that include strong antioxidant, antimutagenic, anti-inflammatory and antiarthritic effects. In the present study, we show that Lupeol possesses antitumor-promoting effects in a mouse skin tumorigenesis model. We first determined the effect of topical application of Lupeol to CD-1 mouse against 12-O-tetradecanoyl-phorbol-13-acetate (TPA)-induced conventional markers and other novel markers of skin tumor promotion. We found that topical application of Lupeol (1-2 mg/mouse) 30 min prior to TPA (3.2 nmol/mouse) application onto the skin of CD-1 mice afforded significant inhibition, in a time- and dose-dependent manner, against TPA-mediated increase in (i) skin edema and hyperplasia, (ii) epidermal ornithine decarboxylase (ODC) activity, and (iii) protein expression of ODC, cyclo-oxygenase-2 and nitric oxide synthase. As of the role of nuclear factor kappa B (NF-kappaB) and phosphatidyl inositol 3-kinase (PI3K)/Akt signaling in tumor promotion, we next determined the effect of topical application of Lupeol to mouse skin against these signaling pathways. We found that Lupeol treatment to mouse skin resulted in the inhibition of TPA-induced (i) activation of PI3K, (ii) phosphorylation of Akt at Thr(308), (iii) activation of NF-kappaB and IKKalpha, and (iv) degradation and phosphorylation of IkappaBalpha. The animals pretreated with Lupeol showed significantly reduced tumor incidence, lower tumor body burden and a significant delay in the latency period for tumor appearance. At the termination of the experiment at 28 weeks, 100% of the animals in TPA-treated group exhibited seven to eight tumors/mouse, whereas only 53% of the mice receiving Lupeol prior to TPA treatment exhibited one to three tumors/mouse. These results for the first time provide evidence that Lupeol possesses antiskin tumor-promoting effects in CD-1 mouse and inhibits conventional as well as novel biomarkers of tumor promotion. We suggest that Lupeol is an attractive antitumor-promoting agent that must be evaluated in tumor models other than skin carcinogenesis.
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PMID:Lupeol modulates NF-kappaB and PI3K/Akt pathways and inhibits skin cancer in CD-1 mice. 1512 42

Protein phosphorylation is a vital process in the regulation of mammalian cell division and the protein kinases that catalyze the phosphorylation of proteins on serine, threonine and tyrosine residues have been well characterized. In contrast, little is known about the kinases involved in protein histidine phosphorylation, which have been described in various mammalian cells that are highly proliferative. Histone H4 histidine kinase (HHK) activity is highly active in regenerating rat liver. Using a novel and specific assay, we demonstrate that it is active in human fetal liver, essentially absent in adult liver and highly expressed in liver tumours. 'Normal' liver surrounding the HCC contains low to undetectable levels of HHK. In a rodent model of chronic liver injury that leads to HCC, its activity is induced. Two lines of evidence suggest that liver progenitor (oval) cells, which populate the liver at early stages following induction of liver damage are responsible for the increased activity. Purified oval cells, as well as cell lines established from primary cultures of oval cells express high levels of HHK. We propose that the pattern of expression of histone H4 histidine kinase activity justifies its classification as an oncodevelopmental marker and suggest it may be useful as a diagnostic marker for hepatocellular carcinoma as well for identifying preneoplastic lesions.
Carcinogenesis 2004 Nov
PMID:Histone H4 histidine kinase displays the expression pattern of a liver oncodevelopmental marker. 1524 May 7

Protein kinase C (PKC), a family of phospholipid-dependent serine/threonine kinases, is not only the major intracellular receptor for the mouse skin tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) but also is activated by a variety of stress factors including ultraviolet radiation (UVR). PKCepsilon is among six isoforms (alpha, delta, epsilon, eta, mu and zeta) expressed in the mouse skin. To determine the in vivo functional specificity of PKCepsilon in mouse skin carcinogenesis, we generated PKCepsilon transgenic mouse (FVB/N) lines 224 and 215 that overexpress PKCepsilon protein approximately 8- and 18-fold, respectively, over endogenous levels in the basal epidermal cells and cells of the hair follicle. PKCepsilon transgenic mice were observed to be highly sensitive to the development of papilloma-independent metastatic squamous cell carcinoma (mSCC) elicited either by repeated exposure to UVR or by the 7,12-Dimethylbenzanthracene-TPA tumor promotion protocol. The development of squamous cell carcinoma (SCC) appears to be linked to the PKCepsilon-mediated induction of cytokine tumor necrosis factor-alpha(TNFalpha). Immunohistochemical analysis for the expression of PKCepsilon in the SCC of PKCepsilon transgenic mice revealed that PKCepsilon was not expressed in the tumor itself; however, the uninvolved tissue surrounding the SCC exhibited intense PKCepsilon expression. Also, human SCC, similar to mouse SCC, did not express PKCepsilon in the tumor, whereas the surrounding uninvolved epidermis revealed strong PKCepsilon expression. These findings in both the PKCepsilon mouse model and human SCC indicate that overexpression of PKCepsilon in epidermis may lead to a microenvironment, which is suitable for enhancing the development of mSCC by a paracrine mechanism involving specific cytokines including TNFalpha.
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PMID:Protein kinase C epsilon signals ultraviolet light-induced cutaneous damage and development of squamous cell carcinoma possibly through Induction of specific cytokines in a paracrine mechanism. 1545 67

Aurora-A, a serine/threonine mitotic kinase, was reported to be overexpressed in various human cancers, and its overexpression induces aneuploidy, centrosome amplification and tumorigenic transformation in cultured human and rodent cells. However, the underlying mechanisms and pathological settings by which Aurora-A promotes tumorigenesis are largely unknown. Here, we created a transgenic mouse model to investigate the involvement of Aurora-A overexpression in the development of mammary glands and tumorigenesis using a Cre-loxP system. The conditional expression of Aurora-A resulted in significantly increased binucleated cell formation and apoptosis in the mammary epithelium. The surviving mammary epithelial cells composed hyperplastic areas after a short latency. Induction of Aurora-A overexpression in mouse embryonic fibroblasts prepared from the transgenic mice also led to aberrant mitosis and binucleated cell formation followed by apoptosis. The levels of p53 protein were remarkably increased in these Aurora-A-overexpressing cells, and the apoptosis was significantly suppressed by deletion of p53. Given that no malignant tumor formation was found in the Aurora-A-overexpressing mouse model after a long latency, additional factors, such as p53 inactivation, are required for the tumorigenesis of Aurora-A-overexpressing mammary epithelium. Our findings indicated that this mouse model is a useful system to study the physiological roles of Aurora-A and the genetic pathways of Aurora-A-induced carcinogenesis.
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PMID:Cre-loxP-controlled periodic Aurora-A overexpression induces mitotic abnormalities and hyperplasia in mammary glands of mouse models. 1548 Apr 17

Chronic exposure to UV radiation (UVR), especially in the UVA (315-400 nm) and UVB (280-315 nm) spectrum of sunlight, is the major risk factor for the development of nonmelanoma skin cancer. UVR is a complete carcinogen, which both initiates and promotes carcinogenesis. We found that protein kinase C epsilon (PKCepsilon), a member of the phospholipid-dependent threonine/serine kinase family, is an endogenous photosensitizer, the overexpression of which in the epidermis increases the susceptibility of mice to UVR-induced cutaneous damage and development of squamous cell carcinoma. The PKCepsilon transgenic mouse (FVB/N) lines 224 and 215 overexpressed 8- and 18-fold PKCepsilon protein, respectively, over endogenous levels in basal epidermal cells. UVR exposure (1 kJ/m(2) three times weekly) induced irreparable skin damage in high PKCepsilon-overexpressing mouse line 215. However, the PKCepsilon transgenic mouse line 224, when exposed to UVR (2 kJ/m(2) three times weekly), exhibited minimum cutaneous damage but increased squamous cell carcinoma multiplicity by 3-fold and decreased tumor latency by 12 weeks. UVR exposure of PKCepsilon transgenic mice compared with wild-type littermates (1) elevated the levels of neither cyclobutane pyrimidine dimer nor pyrimidine (6-4) pyrimidone dimer, (2) reduced the appearance of sunburn cells, (3) induced extensive hyperplasia and increased the levels of mouse skin tumor promoter marker ornithine decarboxylase, and (4) elevated the levels of tumor necrosis factor alpha (TNFalpha) and other growth stimulatory cytokines, granulocyte colony-stimulating factor, and granulocyte macrophage colony-stimulating factor. The role of TNFalpha in UVR-induced cutaneous damage was evaluated using PKCepsilon transgenic mice deficient in TNFalpha. UVR treatment three times weekly for 13 weeks at 2 kJ/m(2) induced severe cutaneous damage in PKCepsilon transgenic mice (line 215), which was partially prevented in PKCepsilon-transgenic TNFalpha-knockout mice. Taken together, the results indicate that PKCepsilon signals UVR-induced TNFalpha release that is linked, at least in part, to the photosensitivity of PKCepsilon transgenic mice.
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PMID:Protein kinase C epsilon is an endogenous photosensitizer that enhances ultraviolet radiation-induced cutaneous damage and development of squamous cell carcinomas. 1552 Jan 80


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