Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Point mutations in the Ras oncogene cause Ras to remain in its active GTP-bound state sending signals downstream continuously. Since 75 to 90% of all human pancreatic ductal adenocarcinomas harbor activating mutations at codon 12 of the K-ras oncogene it was our belief that Raf-1-MEK-MAPK will be activated in the majority of human pancreatic cancers. The aim of this study was to confirm activation of Raf-1 in K-ras mutant human pancreatic cancer. Additionally, we sought to determine if Raf-1 activation differed in K-ras mutant and nonmutant pancreatic cancer. Furthermore, we were interested in determining if Raf-1 activation in pancreatic cancer led to subsequent activation of downstream effectors such as MAP kinase. The presence of mutations in codon 12 of the K-ras oncogene in 14 human pancreatic adenocarcinoma cell lines was determined by use of mutant allele-specific PCR restriction fragment length polymorphism analysis. Raf-1 expression of quiescent cells was determined by immunoblotting using a rabbit anti-human polyclonal antibody and enhanced chemiluminescence. MAP kinase activity was determined by measuring the incorporation of phosphate into Myelin Basic Protein. Seven cell lines were noted to have mutations in codon 12 of K-ras while seven cell lines did not. There was no difference in expression of the 74 kDa-activated form of Raf-1 in K-ras mutant vs K-ras nonmutant cell lines. However, there was a significant increase in MAP kinase activity in the nonmutant cell lines compared to the cell lines with Ras mutations (P = 0.026). We conclude that Raf-1 is expressed in its active form in human pancreatic cancer regardless of K-ras status. However, signalling downstream of Raf-1 differs in cell lines with K-ras mutations compared to those cell lines without K-ras mutations.
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PMID:Activation of Raf-1 in human pancreatic adenocarcinoma. 920 70

Effective chemotherapy for pancreatic cancer is urgently needed. The anti-proliferative activity of a new retinoid, mofarotene (RO40-8757), was compared with that of other retinoids, such as all trans-retinoic acid, 13-cis retinoic acid and 9-cis retinoic acid, on 9 pancreatic cancer cell lines in relation to the effects on various cell cycle-regulating factors. After treatment with each retinoid, anti-proliferative effect was determined by the MTT method and expression of cell cycle-regulating factors, such as cyclins (D1, E and A), cyclin-dependent kinases (2 and 4), cyclin-dependent kinase inhibitors (p21 and p27) and retinoblastoma protein, was analyzed by Western blotting. Mofarotene showed half-maximal inhibition of cell proliferation at concentrations between 0.14 x 10(-6) and 3.8 x 10(-6) mol/l with little cytotoxicity. In contrast, the other retinoids did not inhibit the growth of all cell lines by over 50% compared to controls. A marked increase in the fraction of cells in G1 phase of the cell cycle was observed after mofarotene treatment; this was associated with marked up-regulation of p21/p27 and a shift of retinoblastoma protein into the hypophosphorylated form. In conclusion, mofarotene inhibits the growth of pancreatic cancer cells by inducing G1-phase cell cycle-inhibitory factors (p21, p27 and hypophosphorylated form of Rb protein) and is considered to be a useful agent for pancreatic cancer treatment.
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PMID:Arotinoid mofarotene (RO40-8757) up-regulates p21 and p27 during growth inhibition of pancreatic cancer cell lines. 931 12

To obtain information regarding the growth-inhibitory effect of 1,25-dihydroxyvitamin D3 and its non-calcaemic analogue 22-oxa-1,25-dihydroxyvitamin D3 on pancreatic cancer cell lines, differences in the effects of G1-phase cell cycle-regulating factors were studied in vitamin D-responsive and non-responsive cell lines. Levels of expression of cyclins (D1, E and A), cyclin-dependent kinases (2 and 4) and cyclin-dependent kinase inhibitors (p21 and p27) were analysed by Western blotting after treatment with these compounds. In the responsive cells (BxPC-3, Hs 700T and SUP-1), our observations were: (1) marked up-regulation of p21 and p27 after 24 h treatment with 10(-7) mol l(-1) 1,25-dihydroxyvitamin D3 and 22-oxa-1,25-dihydroxyvitamin D3; and (2) marked down-regulation of cyclins, cyclin-dependent kinases and cyclin-dependent kinase inhibitors after 7 days' treatment. In non-responsive cells (Hs 766T and Capan-1), no such changes were observed. In conclusion, vitamin D analogues up-regulate p21 and p27 as an early event, which in turn could block the G1/S transition and induce growth inhibition in responsive cells.
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PMID:Vitamin D analogues up-regulate p21 and p27 during growth inhibition of pancreatic cancer cell lines. 932 47

AKT2, an oncogene encoding a protein serine-threonine kinase implicated in phosphatidylinositol-3-OH kinase signaling, is amplified in some human ovarian and pancreatic carcinomas. We previously demonstrated that the tumorigenicity and invasiveness of pancreatic ductal adenocarcinoma (PDAC) cell lines with amplified AKT2 could be markedly reduced by transfection with antisense AKT2 constructs. To evaluate further the extent of AKT2 alterations in PDAC, DNA and immunohistochemical analyses were performed to assess amplification or overexpression of AKT2, respectively, in 72 PDACs. Thirty-five PDACs were subjected to Southern analyses, and AKT2 amplification was detected in seven tumors (20%). Forty-one formalin-fixed PDAC specimens were examined immunohistochemically with an anti-AKT2 monoclonal antibody, and moderate to intense staining was observed in eight tumors (20%). AKT2 immunostaining paralleled AKT2 genomic status in each of four cases in which both Southern and immunohistochemical analyses were performed. No obvious relationship was observed between AKT2 status and tumor TNM stage or grade. These observations suggest the utility of immunohistochemical analysis in assessing alterations of AKT2 in human cancers. Furthermore, the role played by the AKT2 kinase in the signaling pathways of various mitogenic growth factors implicated in the development of pancreatic cancer suggests that alteration of AKT2 may be an important component in the pathogenesis of a substantial subset of PDACs.
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PMID:Amplification and overexpression of the AKT2 oncogene in a subset of human pancreatic ductal adenocarcinomas. 949 7

In the present study we investigated the actions of transforming growth factor (TGF)-beta1 on gene induction and cyclin-dependent kinase inhibitors in relation to TGF-beta receptor modulation in COLO-357 pancreatic cancer cells. TGF-beta1 inhibited the growth of COLO-357 cells in a time- and dose-dependent manner and caused a rapid but transient increase in plasminogen activator inhibitor-I and insulin-like growth factor binding protein-3 mRNA levels. TGF-beta1 caused a delayed but sustained increase in the protein levels of the cyclin-dependent kinase inhibitors p15(Ink4B), p21(Cip1), and p27(Kip1) and a sustained increase in type I and II TGF-beta receptors (TbetaRI and TbetaRII) mRNA and protein levels. The protein synthesis inhibitor cycloheximide (10 microg/ml) completely blocked the TGF-beta1-mediated increase in TbetaRI and TbetaRII expression. Furthermore, a nuclear runoff transcription assay revealed that the increase in receptor mRNA levels was due to newly transcribed RNA. There was a significant increase in TbetaRI and TbetaRII mRNA levels in confluent cells in comparison to subconfluent (</=80% confluent) controls, as well as in serum- starved cells when compared with cells incubated in medium containing 10% fetal bovine serum. COLO-357 cells expressed a normal SMAD4 gene as determined by Northern blot analysis and sequencing. These results indicate that TGF-beta1 modulates a variety of functions in COLO-357 cells and up-regulates TGF-beta receptor expression via a transcriptional mechanism, which has the potential to maximize TGF-beta1-dependent antiproliferative responses.
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PMID:Up-regulation of transforming growth factor (TGF)-beta receptors by TGF-beta1 in COLO-357 cells. 951 49

Adenomatous polyposis coli (APC) mutations are present in >70% of colon cancers. The APC protein binds to beta-catenin (beta-cat), a protein first identified because of its role in E-cadherin (E-cad) cell adhesion. In some colon cancers lacking APC defects, mutations in presumptive glycogen synthase kinase 3beta phosphorylation sites near the beta-cat NH2 terminus appear to render beta-cat resistant to regulation by APC and glycogen synthase kinase 3beta. In cells with APC or beta-cat defects, beta-cat is stabilized and, in turn, binds to and activates T-cell factor (Tcf)/lymphoid enhancer factor (Lef) transcription factors. To further explore the role of APC, beta-cat, Tcf, and E-cad defects in gastrointestinal cancers, we assessed gastric and pancreatic cancers for constitutive Tcf transcriptional activity (CTTA). Two of four gastric and two of eight pancreatic cancer lines showed CTTA. One gastric and one pancreatic cancer had mutations in the NH2-terminal phosphorylation sites of beta-cat. The other gastric cancer with CTTA had a missense mutation at serine 28 of gamma-cat, a potential phosphorylation site in this beta-cat-related protein. Although E-cad is an important binding partner for beta-cat and gamma-cat, E-cad inactivation did not result in CTTA. The beta-cat and gamma-cat mutant proteins identified in our studies strongly activated Tcf transcription in vitro, whereas beta-cat mutant proteins with large NH2-terminal deletions had only modest effects on Tcf. Our results suggest a role for Tcf deregulation in gastric and pancreatic cancer, resulting from beta-cat and gamma-cat mutations in some cases and, in others, from yet to be defined defects. Furthermore, these data imply that the consequences of APC and beta-cat mutations are distinct from the effects of E-cad inactivation.
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PMID:Beta- and gamma-catenin mutations, but not E-cadherin inactivation, underlie T-cell factor/lymphoid enhancer factor transcriptional deregulation in gastric and pancreatic cancer. 1039 98

Although the first English-language report of melanoma in 1820 contained a description of a melanoma-prone family, it was 1983 before formal genetic analysis suggested an autosomal dominant mode of inheritance for both melanoma and the then newly described melanoma precursor, dysplastic nevi (DN). Subsequent genetic studies have assumed this model to be correct, although when viewed in aggregate, the data are inconsistent. The first proposed melanoma gene (CMM1) was mapped to chromosome 1p36. This gene assignment has not been confirmed. A second melanoma gene, designated CMM2, has been mapped to chromosome 9p21. This gene assignment has been confirmed, and the cell cycle regulator CDKN2A has been proposed as the candidate gene. Germline mutations in this gene have been identified in about 20% of melanoma-prone families that have been studied to date. Pancreatic cancer occurs excessively in melanoma families with germline mutations in CDKN2A. Germline mutations in the cyclin-dependent kinase gene CDK4 (chromosome 12q14) have been described in three melanoma families. This finding represents a third melanoma gene but one that accounts for only a tiny fraction of all hereditary melanoma. Recently, a familial melanoma-astrocytoma syndrome has been reported. Large germline deletions of 9p21 occur in these families, with the p19 gene implicated in its pathogenesis. At present, clinical predictive genetic testing for mutations in the CDKN2A gene is available commercially, but its use has been limited by uncertainty as to how test results would affect the management of melanoma-prone family members. Currently, management recommendations include monthly skin self-examination, clinical skin examination once or twice yearly, a low threshold for simple excision of changing pigmented lesions, moderation of sun exposure, and appropriate use of sunscreens. A heritable determinant for total nevus number has been suggested by twin studies. Other data suggest the presence of a major gene responsible for "total nevus density" in melanoma-prone families. Approximately 55% of the mole phenotype in multiplex melanoma families was explained by this proposed gene. An autosomal dominant mode of inheritance has been proposed for DN, and data exist to suggest that DN may be a pleiotropic manifestation of the 1p36 familial melanoma gene. However, there clearly are melanoma-prone families that do not express the dysplastic nevus trait, and some of the families linked to CDKN2A also present with dysplastic nevi. Several studies have shown a surprisingly high prevalence of DN on the skin of family members of probands with DN. In light of the extensive evidence documenting that persons with DN (both sporadic and familial) have an increased prospective risk of melanoma, these family studies suggest that relatives of persons with DN should be examined for both DN and melanoma. Genetic determinants play a major role in the pathogenesis of normal nevi, DN, and melanoma. Identifying the molecular basis of these genetic events promises to enhance melanoma risk-reduction strategies and, ultimately, reduce melanoma-associated mortality.
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PMID:The genetics of hereditary melanoma and nevi. 1998 update. 1063 Jan 72

The carbohydrate antigen sialyl-Lewis(a) is important to pancreatic tumour biology because the circulating antigen is used in serological tests for malignancy and because cell surface antigen is involved in tumour cell binding to the endothelial adhesion molecule, E-selectin, in extravasation. In this study, we examined the effects of the adenylyl cyclase activator, forskolin, and the diacylglycerol analogue, phorbol 12-myristate 13-acetate (PMA), on the expression and release of sialyl-Lewis(a) in human pancreatic cancer cells. Increases in the release of sialyl-Lewis(a) from SW1990 cells produced by forskolin and PMA were associated with increases in the activities of protein kinases A and C, respectively, and could be blocked by inhibitors specific for these enzymes. Immunoprecipitation experiments showed that sialyl-Lewis(a) was associated with MUC1 mucin. Forskolin also increased the cellular content of antigen and MUC1 mRNA. Actinomycin D and a protein kinase A inhibitor, H8, blocked these effects. In contrast, PMA reduced cellular antigen and MUC1 mRNA levels, although it produced a temporary increase in release of the antigen. The effects of PMA were blocked by the protein kinase C inhibitor, H7. PMA also reduced cell binding to the adhesion molecule E-selectin. In summary, PKA and PKC alter cell MUC1-associated sialyl-Lewis(a) in opposite directions. These changes may have clinical utility in the diagnosis of pancreatic cancer and the prevention of metastases.
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PMID:Forskolin and phorbol ester have opposite effects on the expression of mucin-associated sialyl-Lewis(a) in pancreatic cancer cells. 1074 4

We have analyzed human pancreatic cancer cells to explore the growth regulatory function of protein kinase C (PKC)alpha. PKCalpha subcellular redistribution, activation kinetics and downregulation were examined in detail and correlated to immediate and delayed effects on cell-cycle regulatory pathways. TPA treatment resulted in transient PKC(&agr;) activation accompanied by translocation of the enzyme into membrane and nuclear compartments, and was followed by subsequent downregulation. TPA-induced inhibition of DNA synthesis was prevented by a PKC-antagonist and was reproduced by microinjection of recombinant PKCalpha, indicating that activation of this isoenzyme was required and sufficient for growth inhibitory effects. PKC(&agr;) activation arrested cells in the G(1) phase of the cell cycle as a consequence of selective inhibition of cyclin dependent kinase (CDK)2 activity with concomitant hypophosphorylation of Rb. The inhibition of CDK2 activity resulted from induction of p21(cip1) cyclin-dependent kinase inhibitors. Levels of p21(cip1) remained elevated and CDK2 activity repressed in spite of PKCalpha downregulation, indicating that downstream effectors of PKCalpha are the primary determinants for the duration of PKC-mediated growth inhibition. The PKCalpha-induced block in cell proliferation persisted even though cells were kept in the presence of growth factors, suggesting that induction of PKCalpha results in a permanent withdrawal of pancreatic cancer cells from the cell cycle.
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PMID:Activation of protein kinase Calpha inhibits growth of pancreatic cancer cells via p21(cip)-mediated G(1) arrest. 1093 41

In the present study, we examine whether human pancreatic carcinoma cells express peroxisome proliferator-activated receptor gamma (PPARgamma) and the effect of PPARgamma activation by its selective ligand on cellular growth in pancreatic cancer cells. Immunohistochemical study of resected human pancreata using a polyclonal PPARgamma antibody revealed that PPARgamma protein expression in the nuclei of carcinoma cells was observed in 9 of 10 pancreatic adenocarcinomas. In contrast, normal pancreatic duct epithelial cells in the samples expressed no PPARgamma. Reverse transcription-PCR and Northern blot analysis demonstrated that all four tested human pancreatic cancer cell lines, PK-1, PK-8, PK-9, and MIA Paca-2, expressed PPARgamma mRNA. Luciferase assay in PK-1 cells showed that troglitazone, a selective ligand for PPARgamma, transactivated the transcription of a peroxisome proliferator response element-driven promoter in a dose-dependent fashion. Troglitazone inhibited the growth of all four pancreatic carcinoma cell lines in a dose-dependent manner. Cell cycle analysis by flow cytometry demonstrated that troglitazone induced G1 arrest in PK-1 cells. To examine the role of cyclin-dependent kinase inhibitors in the G1 arrest by troglitazone, we determined p27KiP1, p21CiP1/Waf1, or p18Ink4c protein expression by Western blot analysis in troglitazone-treated PK-1 cells. Troglitazone increased p27Kip1 but not p21Cip1/Waf1 or p18Inkc protein levels in time- and dose-dependent manners. To clarify the functional importance of p27Kip1 in the cell growth inhibition by troglitazone. All these results suggest that PPARgamma could be considered as a possible target molecule for treatment in human pancreatic carcinomas.
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PMID:Activation of peroxisome proliferator-activated receptor gamma by troglitazone inhibits cell growth through the increase of p27KiP1 in human. Pancreatic carcinoma cells. 1103 3


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