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: UMLS:C0699790 (colon cancer)
28,837 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Activated c-raf(-1) gene was found in three transformants obtained by transfecting DNAs from rat hepatocellular carcinoma, metastasis of human colon cancer in mesocolon and normal mucosa from a different colon cancer patient. Rat and human activated c-raf(-1) genes were cloned into cosmid vectors; restriction enzyme mapping revealed both activated c-raf(-1) genes to have rearrangement in the center of the normal form of the gene, and the upstream sequences were replaced by unrelated sequences. Using genomic DNA fragments located immediately downstream of the recombination points, the activations of all these c-raf(-1) were shown to have occurred during the transfection process. The recombination points in both the rat and human clones isolated were located in the intron between exons 7 and 8, and nucleotide sequencing around these recombination points showed there to be an inverted repeat which could be involved in inducing in vitro recombination. Nucleotide sequencing of rat and human c-raf(-1) cDNAs revealed the upstream sequences, recombined to the 3' half of c-raf(-1), to be expressed as fusion mRNAs; the production of fused proteins was predicted from a long open reading frame, which is in-frame with the kinase domain encoded from the 3' half of the c-raf(-1) gene. There is a cysteine clustering region in an N-terminal region of the c-raf(-1) product deduced from the nucleotide sequence, and this cysteine clustering region was found to be highly homologous to that present in an N-terminal region of protein kinase C, although, in the latter cysteine clusters are present in duplicate. From analogy with the activation mechanism of protein kinase C, the N-terminal region of serine/threonine kinase coded by the c-raf(-1) gene is suggested to be a regulatory part of the enzyme activity, and it proposed that the replacement or truncation of this regulatory part could be the mechanism whereby c-raf(-1) is activated.
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PMID:Activation of rat and human c-raf(-1) by rearrangement. 333 22

LKB1 serine/threonine kinase is a gene for Peutz-Jeghers cancer predisposition syndrome. Most studies have detected a low frequency of LKB1 defects in sporadic cancer. A notable exception is a recent report describing frequent, mostly missense type, LKB1 mutations in Korean distal colorectal tumors. To clarify the role of LKB1 in colon cancer, we scrutinized 50 left-sided Korean and Finnish specimens. No somatic mutations were found. The seven Korean somatic missense mutations reported previously were functionally analyzed, and five were found not to alter LKB1 kinase activity. One of these changes was found to be a germ-line polymorphism. LKB1 involvement in distal colorectal cancer is not common.
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PMID:No evidence of Peutz-Jeghers syndrome gene LKB1 involvement in left-sided colorectal carcinomas. 1067 34

Protocadherins are a major subfamily of the cadherin superfamily, but little is known about their functions and intracellular signal transduction. We cloned a novel human protocadherin gene, containing seven EC domains, and identified functional aspects of this gene. The gene was predominantly expressed in liver, kidney and colon tissues, and was thus designated Protocadherin LKC. The expression of Protocadherin LKC is markedly reduced in cancers arising from these tissues at both transcriptional and protein levels. To investigate the effects of Protocadherin LKC expression in colon cancer, we introduced the gene into colon cancer cell line HCT116, which does not express this gene. Significantly, Protocadherin LKC expression induced contact inhibition of cell proliferation although it did not affect growth rate. When grown to post-confluence in monolayer cells cultures, Protocadherin LKC-expressing HCT116 no longer formed multiple cell layers and showed the typical paving stone morphology of normal epithelial cells. Furthermore, expression of Protocadherin LKC suppressed tumor formation of HCT116 cells in a nude mouse model. In addition, we identified a protein, hMAST205 (microtubule-associated serine/threonine kinase-205 kDa), which interacted with Protocadherin LKC; the interaction occurring between the PDZ domain of hMAST205 and C-terminal tail of Protocadherin LKC. Our results suggest that Protocadherin LKC, which directly binds PDZ protein, is a molecular switch for contact inhibition of epithelial cells in the liver, kidney and colon tissues.
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PMID:Protocadherin LKC, a new candidate for a tumor suppressor of colon and liver cancers, its association with contact inhibition of cell proliferation. 1211 71

Deregulation of Wnt/beta-catenin signaling is thought to play a critical role in human carcinogenesis. Nemo-like kinase (NLK) is an evolutionarily conserved serine/threonine kinase that suppresses beta-catenin/T-cell factor (TCF) complex transcriptional activity through phosphorylation of TCF. Since NLK may be a tumor suppressor as a negative regulator of Wnt/beta-catenin pathway, we established tetracycline-inducible NLK and its kinase-negative mutant expression in DLD-1 human colon cancer cells to analyze the effect of NLK on cell growth and viability. The induction of wild-type NLK in DLD-1 cells caused suppression of cell growth whereas the kinase-negative mutant did not. Flow cytometry indicated that NLK expression increased the number of apoptotic cells but did not induce obvious cell cycle arrest. Apoptosis induction by wild-type NLK was confirmed using TUNEL assays. Our results suggest that overexpression of NLK may have targets other than TCF for induction of apoptosis in human colon carcinoma cells.
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PMID:Nemo-like kinase induces apoptosis in DLD-1 human colon cancer cells. 1290 58

Nemo-like kinase (NLK) is a serine/threonine kinase that suppresses the transcription activity of the beta-catenin-T-cell factor (TCF) complex through phosphorylation of TCF. Our previous study showed that NLK overexpression induces apoptosis in DLD-1 human colon cancer cells and that apoptosis induction presumably requires a mechanism other than the suppression of beta-catenin-TCF complex. Luciferase reporter gene assay with pNF-kappaB-Luc revealed that NLK could suppress transcription activity of NF-kappaB in a kinase-dependent manner. However, it appeared that transcription co-activators of NF-kappaB, such as CREB binding protein (CBP)/p300, were likely to be the direct targets of NLK, rather than NF-kappaB itself. Luciferase reporter gene analysis of GAL4-CBP fusion proteins revealed that the C-terminal region of CBP was critical for transcription suppression by NLK. In vitro kinase assay showed that NLK could phosphorylate the C-terminal domain of CBP. However, HAT activity was not suppressed by the induction of wild-type NLK in DLD-1 cells. Furthermore, we observed that NLK suppressed the transcription activity of AP-1, Smad, and p53, all of which also utilize CBP as a co-activator. The extent of suppression by NLK was similar among the transcription factors tested (50-60% reduction). Our results suggest that NLK may suppress a wide range of gene expression, possibly through CBP.
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PMID:Nemo-like kinase suppresses a wide range of transcription factors, including nuclear factor-kappaB. 1472 Mar 27

Akt, a serine/threonine kinase that promotes cell survival, is activated by binding of its pleckstrin homology (PH) domain to membrane phosphatidylinositol (PtdIns)-3-phosphates formed by PtdIns-3-kinase. D-3-Deoxy-phosphatidyl-myo-inositols that cannot be phosphorylated on the 3-position of the myo-inositol group are inhibitors of the Akt PH domain. The most active compound is D-3-deoxy-phosphatidyl-myo-inositol 1-[(R)-2-methoxy-3-octadecyloxypropyl hydrogen phosphate] (PX-316). PX-316 administered intraperitoneally to mice at 150 mg/kg inhibits Akt activation in HT-29 human tumor xenografts up to 78% at 10 h with recovery to 34% at 48 h. Phosphorylation of GSK-3beta, a downstream target of Akt, is also inhibited. There is no decrease in PtdIns(3,4,5)-trisphosphate levels by PX-316, showing it is not an inhibitor of PtdIns-3-K in vivo. Gene expression profiling of HT-29 tumor xenografts shows many similarities between the effects of PX-316 and the PtdIns-3-K inhibitor wortmannin, with downregulation of several ribosomal-related genes, while PX-316 uniquely increases the expression of a group of mitochondrial-related genes. PX-316 has antitumor activity against early human MCF-7 breast cancer and HT-29 colon cancer xenografts in mice. PX-316 formulated in 20% hydroxypropyl-beta-cyclodextrin for intravenous administration is well tolerated in mice and rats with no hemolysis and no hematological toxicity. Thus, PX-316 is the lead compound of a new class of potential agents that inhibit Akt survival signaling.
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PMID:In vivo molecular pharmacology and antitumor activity of the targeted Akt inhibitor PX-316. 1555 65

The serine/threonine kinase AKT plays a critical role in controlling the balance between cell survival and apoptosis. Several reports implicated AKT in the molecular pathogenesis of different human malignancies and overexpression of AKT was recently demonstrated to be an early event in colorectal carcinogenesis. We report here the identification of nine putative Tcf/Lef-binding elements (TBEs) upstream to the ATG initiation site of the AKT1 gene. Four of these TBEs are located upstream of the transcriptional start, whereas five TBEs are situated in Exon 1 of the AKT1 gene. Accordingly, we hypothesized that AKT1 expression might be regulated by Wnt/beta-catenin signaling. To elucidate the regulation of AKT expression in colon cancer cells, we generated reporter constructs containing the luciferase gene under the control of different regions derived from the AKT1 promoter/enhancer. Transient expression of the constructs in colorectal cancer (CRC) cell lines resulted in significant activation of the reporter gene. Luciferase was stimulated 20- to 50-fold in SW480, SW948 and HCT116 CRC cells. In contrast, the AKT1 promoter/enhancer constructs showed only a weak response in 293 embryonic kidney cells. Coexpression of a constitutively active beta-catenin mutant in colon cancer cells further enhanced reporter gene activation from the AKT1 promoter/enhancer, whereas it was downregulated by introduction of either wild-type APC or dnTcf-4. In addition, immunohistochemical staining of tumor sections derived from CRC patients showed elevated expression levels of AKT1, correlating with enhanced cytoplasmic/nuclear expression of beta-catenin. In summary our data suggest that beta-catenin/Tcf contributes to the transcriptional regulation of the AKT1 gene.
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PMID:Regulation of AKT1 expression by beta-catenin/Tcf/Lef signaling in colorectal cancer cells. 1588 91

PKC-delta is a serine/threonine kinase that mediates diverse signal transduction pathways. We previously demonstrated that overexpression of PKC-delta slowed the G1 progression of Caco-2 colon cancer cells, accelerated apoptosis, and induced cellular differentiation. In this study, we further characterized the PKC-delta dependent signaling pathways involved in these tumor suppressor actions in Caco-2 cells overexpressing PKC-delta using a Zn2+ inducible expression vector. Consistent with a G1 arrest, increased expression of PKC-delta caused rapid and significant downregulation of cyclin D1 and cyclin E proteins (50% decreases, P<0.05), while mRNA levels remained unchanged. The PKC agonist, phorbol 12-myristate 13-acetate (TPA, 100 nM, 4 h), induced two-fold higher protein and mRNA levels of p21(Waf1), a cyclin-dependent kinase (cdk) inhibitor in PKC-delta transfectants compared with empty vector (EV) transfected cells, whereas the PKC-delta specific inhibitor rottlerin (3 microM) or knockdown of this isoenzyme with specific siRNA oligonucleotides blocked p21(Waf1) expression. Concomitantly, compared to EV control cells, PKC-delta upregulation decreased cyclin D1 and cyclin E proteins co-immunoprecipitating with cdk6 and cdk2, respectively. In addition, overexpression of PKC-delta increased binding of cdk inhibitor p27(Kip1) to cdk4. These alterations in cyclin-cdks and their inhibitors are predicted to decrease G1 cyclin kinase activity. As an independent confirmation of the direct role PKC-delta plays in cell growth and cell cycle regulation, we knocked down PKC-delta using specific siRNA oligonucleotides. PKC-delta specific siRNA oligonucleotides, but not irrelevant control oligonucleotides, inhibited PKC-delta protein by more than 80% in Caco-2 cells. Moreover, PKC-delta knockdown enhanced cell proliferation ( approximately 1.4-2-fold, P<0.05) and concomitantly increased cyclin D1 and cyclin E expression ( approximately 1.7-fold, P<0.05). This was a specific effect, as nontargeted PKC-zeta was not changed by PKC-delta siRNA oligonucleotides. Consistent with accelerated apoptosis in PKC-delta transfectants, compared to EV cells, PKC-delta upregulation increased proapoptotic regulator Bax two-fold at mRNA and protein levels, while antiapoptotic Bcl-2 protein was decreased by 50% at a post-transcriptional level. PKC-delta specific siRNA oligonucleotides inhibited Bax protein expression by more than 50%, indicating that PKC-delta regulates apoptosis through Bax. Taken together, these results elucidate two critical mechanisms regulated by PKC-delta that inhibit cell cycle progression and enhance apoptosis in colon cancer cells. We postulate these antiproliferative pathways mediate an important tumor suppressor function for PKC-delta in colonic carcinogenesis.
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PMID:Protein kinase C delta inhibits Caco-2 cell proliferation by selective changes in cell cycle and cell death regulators. 1643 69

We previously observed that Pim-3 with serine/threonine kinase activity, was aberrantly expressed in malignant lesions of endoderm-derived organs, liver and pancreas. Because Pim-3 protein was not detected in normal colon mucosal tissues, we evaluated Pim-3 expression in malignant lesions of human colon, another endoderm-derived organ. Pim-3 was detected immunohistochemically in well-differentiated (43/68 cases) and moderately differentiated (23/41 cases) but not poorly differentiated colon adenocarcinomas (0/5 cases). Moreover, Pim-3 proteins were detected in adenoma (35/40 cases) and normal mucosa (26/111 cases), which are adjacent to adenocarcinoma. Pim-3 was constitutively expressed in SW480 cells and the transfection with Pim-3 short hairpin RNA promoted apoptosis. In the same cell line, a pro-apoptotic molecule, Bad, was phosphorylated at Ser(112) and Ser(136) sites of phosphorylation that are representative of its inactive form. Ser(112) but not Ser(136) phosphorylation in this cell line was abrogated by Pim-3 knockdown. Furthermore, in human colon cancer tissues, Pim-3 co-localized with Bad in all cases (9/9) and with phospho-Ser(112)Bad in most cases (6/9). These observations suggest that Pim-3 can inactivate Bad by phosphorylating its Ser(112) in human colon cancer cells and thus may prevent apoptosis and promote progression of human colon cancer.
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PMID:Proto-oncogene, Pim-3 with serine/threonine kinase activity, is aberrantly expressed in human colon cancer cells and can prevent Bad-mediated apoptosis. 1727 21

Resveratrol has been reported to possess therapeutic effects for various cancers including colon cancers. In this article, the molecular basis of resveratrol with emphasis on its ability to control intracellular signaling cascades of adenosine monophosphate (AMP)-activated protein kinase (AMPK) responsible for inducing apoptosis in drug-resistant cancer cells was investigated. Recently, the evolutionarily conserved serine/threonine kinase, AMPK, emerges as a possible target molecule of cancer control. We have investigated the effects of resveratrol on apoptosis in relation to AMPK in HT-29 cells shown chemoresistant to a cancer chemotherapeutic drug, etoposide. Resveratrol exhibited a variety of molecular events in etoposide-based combination therapy in HT-29 colon cancer cells including the AMPK activation, inhibition of cell growth, induction of apoptosis, and reactive oxygen species (ROS) generation. The involvement of AMPK signaling cascade in resveratrol-based cancer therapy was clearly shown by comparing the conditions of AMPK activated states and inactivated states. We have identified ROS as an upstream regulator of AMPK. Further investigation warrants to elucidate the mechanism by which resveratrol generates ROS and AMPK activation.
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PMID:Resveratrol induces apoptosis in chemoresistant cancer cells via modulation of AMPK signaling pathway. 1740 56


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