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)

Macroautophagy or autophagy is an ubiquitous and conserved degradative pathway of cytosolic components, macromolecules or organelles, into the lysosome. By using biochemical and microscopic methods, which allow one to measure the rate of autophagy, the role of two regulators of Gi3 protein activity, activator of G-protein-signaling-3 (AGS3) and Galpha-interacting protein (GAIP), was studied in the control of autophagy in human colon cancer HT-29 cells. In HT-29 cells, autophagy is under the control of the Gi3 protein and, when bound to the GTP, the Galphai3 protein inhibits autophagy, whereas it stimulates autophagy when bound to the GDP. GAIP, which enhances the intrinsic GTPase-activating protein activity of the Galphai3 protein, stimulates autophagy by favoring the GDP-bound form of Galphai3. We showed that GAIP is phosphorylated on its serine 151 and that this phosphorylation is dependent on the presence of amino acids that modulate Raf-1 activity, the kinase upstream of Erk1/2. AGS3, a guanine nucleotide dissociation inhibitor, stimulates autophagy by binding Galphai3 proteins. The intracellular localization of AGS3 (Golgi apparatus and endoplasmic reticulum, two membranes known to be at the origin of autophagosomes) is consistent with its role in autophagy.
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PMID:Analyses of Galpha-interacting protein and activator of G-protein-signaling-3 functions in macroautophagy. 1548 68

Cyclooxygenase-derived prostaglandin E(2) (PGE(2)) stimulates tumor progression by modulating several proneoplastic pathways. The mechanisms by which PGE(2) promotes tumor growth and metastasis through stimulation of cell migration, invasion, and angiogenesis have been fairly well characterized. Much less is known, however, about the molecular mechanisms responsible for the immunosuppressive effects of PGE(2). We identified PGE(2) target genes and subsequently studied their biologic role in colorectal cancer cells. The complement regulatory protein decay-accelerating factor (DAF or CD55) was induced following PGE(2) treatment of LS174T colon cancer cells. Analysis of PGE(2)-mediated activation of the DAF promoter employing 5'-deletion luciferase constructs suggests that regulation occurs at the transcriptional level via a cyclic AMP/protein kinase A-dependent pathway. Nonsteroidal anti-inflammatory drugs blocked DAF expression in HCA-7 colon cancer cells, which could be restored by the addition of exogenous PGE(2). Finally, we observed an increase in DAF expression in the intestinal mucosa of Apc(Min+/-) mice treated with PGE(2) in vivo. In summary, these results indicate a novel immunosuppressive role for PGE(2) in the development of colorectal carcinomas.
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PMID:Prostaglandin E2 regulates the complement inhibitor CD55/decay-accelerating factor in colorectal cancer. 1552 8

Mice lacking both p18(Ink4c) and p27(Kip1) develop a tumor spectrum similar to pRb(+/-) mice, and loss of p53 function accelerates tumorigenesis in pRb(+/-) mice. We hypothesized that codeletion of either p18 or p27 in conjunction with p53 deletion will also accelerate tumorigenesis. Mice lacking both p18 and p53 develop several tumors not reported in either single null genotype, including hepatocellular carcinoma, testicular choriocarcinoma, hemangiosarcoma, leiomyosarcoma, fibrosarcoma, and osteosarcoma. Mice lacking both p27 and p53 exhibit a decreased lifespan and develop unique tumors, including papillary carcinoma of the colon, hemangiosarcoma, and leiomyosarcoma. In both p18/p53 and p27/p53 double null genotypes, the incidence and spectra of tissues that develop lymphoma are also increased, as compared to the single null genotypes. The development of p27/p53 double null colon tumors correlates with secondary changes in cell-cycle protein expression and CDK (cyclin-dependent kinase) activity, perhaps contributing to the progression of colorectal cancer. We concluded that p18 and p27 can, not only functionally collaborate with one another, but also can independently collaborate with p53 to modulate the cell cycle and suppress tumorigenesis in a tissue-specific manner.
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PMID:Tumorigenesis in p27/p53- and p18/p53-double null mice: functional collaboration between the pRb and p53 pathways. 1558 24

Various proteases are involved in cancer progression and metastasis. In particular, gelatinases, matrix metalloproteinase-2 (MMP-2) and MMP-9, have been implicated to play a role in colon cancer progression and metastasis in animal models and patients. In the present review, the clinical relevance and the prognostic value of messenger ribonucleic acid (mRNA) and protein expression and proenzyme activation of MMP-2 and MMP-9 are evaluated in relation to colorectal cancer. Expression of tissue inhibitors of MMPs (TIMPs) in relation with MMP expression in cancer tissues and the relevance of detection of plasma or serum levels of MMP-2 and/or MMP-9 and TIMPs for prognosis are also discussed. Furthermore, involvement of MMP-2 and MMP-9 in experimental models of colorectal cancer is reviewed. In vitro studies have suggested that gelatinase is expressed in cancer cells but animal models indicated that gelatinase expression in non-cancer cells in tumors contributes to cancer progression. In fact, interactions between cancer cells and host tissues have been shown to modulate gelatinase expression in host cells. Inhibition of gelatinases by synthetic MMP inhibitors has been considered to be an attractive approach to block cancer progression. However, despite promising results in animal models, clinical trials with MMP inhibitors have been disappointing so far. To obtain more insight in the (patho)physiological functions of gelatinases, regulation of MMP-2 and MMP-9 expression is discussed. Mitogen activated protein kinase (MAPK) signalling has been shown to be involved in regulation of gelatinase expression in both cancer cells and non-cancer cells. Expression can be triggered by a variety of stimuli including growth factors, cytokines and extracellular matrix (ECM) components. On the other hand, MMP-2 and MMP-9 activity regulates bioavailability and activity of growth factors and cytokines, affects the immune response and is involved in angiogenesis. Because of the multifunctionality of gelatinases, it is unpredictable at what stage of cancer development and in which processes gelatinase activity is involved. Therefore, it is concluded that the use of MMP inhibitors to treat cancer should be considered carefully.
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PMID:The role of gelatinases in colorectal cancer progression and metastasis. 1558 63

Recent studies show that the human parathyroid calcium sensing receptor (CaSR) is expressed in human colon epithelium and functions to regulate epithelial proliferation and differentiation. In this study, we show that the cells of the colon crypt acquire CaSR expression as they differentiate and migrate towards the apex of the crypt. CaSR expression was weak in colon carcinomas with a more-differentiated histologic pattern, whereas CaSR expression was undetectable in less-differentiated tumors. We found that Ca(2+) and/or 1,25(OH)(2)D(3) stimulated CaSR promoter activity and CaSR protein expression in the human colon carcinoma CBS cells, which possessed a functional CaSR. Both agents concomitantly induced a series of changes in the CBS cells that influence proliferation and differentiation, but cellular responses to the two agents were not identical. Ca(2+) strongly induced E-cadherin expression and inhibited the expression of the nuclear transcription factor, TCF4. 1,25(OH)(2)D(3) was weaker in its effect on E-cadherin and was not able to inhibit TCF4 expression. 1,25(OH)(2)D(3) was as strong or stronger than Ca(2+) in its induction of the cyclin-dependent kinase inhibitors, P21 and p27. It is concluded that CaSR may function in the colon to regulate epithelial differentiation and that loss of CaSR expression may be associated with abnormal differentiation and/or malignant progression. Extracellular Ca(2+) and 1,25(OH)(2)D(3) are potential candidates involved in regulating CaSR expression in the colon and the chemopreventive actions of Ca(2+) and 1,25(OH)(2)D(3) in colon cancer may be mediated, in part, through the CaSR.
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PMID:Calcium sensing receptor in human colon carcinoma: interaction with Ca(2+) and 1,25-dihydroxyvitamin D(3). 1569 91

Beta-catenin is a multifunctional protein serving both as a structural element in cell adhesion and as a signaling component in the Wnt pathway, regulating embryogenesis and tumorigenesis. The signaling fraction of beta-catenin is tightly controlled by the adenomatous polyposis coli-axin-glycogen synthase kinase 3beta complex, which targets it for proteasomal degradation. It has been recently shown that Ca(2+) release from internal stores results in nuclear export and calpain-mediated degradation of beta-catenin in the cytoplasm. Here we have highlighted the critical relevance of constitutive calpain pathway in the control of beta-catenin levels and functions, showing that small interference RNA knock down of endogenous calpain per se (i.e. in the absence of external stimuli) induces an increase in the free transcriptional competent pool of endogenous beta-catenin. We further characterized the role of the known calpain inhibitors, Gas2 and Calpastatin, demonstrating that they can also control levels, function, and localization of beta-catenin through endogenous calpain regulation. Finally we present Gas2 dominant negative (Gas2DN) as a new tool for regulating calpain activity, providing evidence that it counteracts the described effects of both Gas2 and Calpastatin on beta-catenin and that it works via calpain independently of the classical glycogen synthase kinase 3beta and proteasome pathway. Moreover, we provide in vitro biochemical evidence showing that Gas2DN can increase the activity of calpain and that in vivo it can induce degradation of stabilized/mutated beta-catenin. In fact, in a context where the classical proteasome pathway is impaired, as in colon cancer cells, Gas2DN biological effects accounted for a significant reduction in proliferation and anchorage-independent growth of colon cancer.
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PMID:The calpain system is involved in the constitutive regulation of beta-catenin signaling functions. 1581 86

Recent studies suggest that lysophosphatidic acid (LPA) and its G protein-coupled receptors (GPCRs) LPA(1), LPA(2), or LPA(3) may play a role in the development of several types of cancers, including colorectal cancer. However, the specific receptor subtype(s) and their signal-transduction pathways responsible for LPA-induced cancer cell proliferation have not been fully elucidated. We show by specific RNA interference (RNAi) that LPA(2) and LPA(3) but not LPA(1) are targets for LPA-induced proliferation of HCT116 and LS174T colon cancer cells. We determined that LPA-induced colon cancer cell proliferation requires the beta-catenin signaling pathway, because knockdown of beta-catenin by RNAi abolished LPA-induced proliferation of HCT116 cells. Moreover, LPA activates the main signaling events in the beta-catenin pathway: phosphorylation of glycogen synthase kinase 3beta (GSK3beta), nuclear translocation of beta-catenin, transcriptional activation of T cell factor (Tcf)/lymphoid-enhancer factor (Lef), and expression of target genes. Inhibition of conventional protein kinase C (cPKC) blocked the effects, suggesting its involvement in LPA-induced activation of the beta-catenin pathway. Thus, LPA(2) and LPA(3) signal the proliferation of colon cancer cells through cPKC-mediated activation of the beta-catenin pathway. These results link LPA and its GPCRs to cancer through a major oncogenic signaling pathway.
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PMID:G protein-coupled lysophosphatidic acid receptors stimulate proliferation of colon cancer cells through the {beta}-catenin pathway. 1583 31

WNKs are large serine/threonine protein kinases structurally distinct from all other members of the protein kinase superfamily. Of the four human WNK family members, WNK1 and WNK4 have been linked to a hereditary form of hypertension, pseudohypoaldosteronism type II. We characterized the biochemical properties and regulation of WNK1 that may contribute to its physiological activities and abnormal function in disease. We showed that WNK1 is activated by hypertonic stress in kidney epithelial cells and in breast and colon cancer cell lines. In addition, hypotonic stress also led to a modest increase in WNK1 activity. Gel filtration suggested that WNK1 exists as a tetramer, and yeast two-hybrid data showed that the N terminus of WNK1 (residues 1-222) interacts with residues 481-660, which includes the WNK1 autoinhibitory domain and a C-terminal coiled-coil domain. Although cell biological studies have suggested a functional interaction between WNK1 and WNK4, we found no evidence of stable interactions between these kinases. However, WNK1 phosphorylated both WNK4 and WNK2. In addition, the WNK1 autoinhibitory domain inhibited the catalytic activity of these WNKs. These findings suggest potential mechanisms for interconnected regulation of WNK family members.
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PMID:Properties of WNK1 and implications for other family members. 1588 53

Cyclooxygenase and its derived prostaglandin E2 (PGE2) have been shown to stimulate the growth of cancer cells and promote tumor angiogenesis. Here, we show that PGE2 activated the beta-catenin/T cell factor-dependent transcription in colon cancer cells through the cAMP/protein kinase A pathway. The expression of cyclin D1 and vascular endothelial growth factor was induced by PGE2 in LS-174T cells. Moreover, PGE2 and mutated beta-catenin stimulated the transcription of cyclin D1 and vascular endothelial growth factor in a synergistic fashion. Mechanistically, PGE2 increased the phosphorylation of glycogen synthase kinase-3 and consequently accumulated beta-catenin. In addition, PGE2 induced the expression of T cell factor-4 transcription factor, which formed transcriptionally active complex with beta-catenin. In animal experiments, administration of 16,16-dimethyl PGE2 strongly increased the expression of cyclin D1 and vascular endothelial growth factor in APC(min/+) mouse polyps. Thus, our results provide a novel mechanism, suggesting that cyclooxygenase-2/PGE2 may exert pro-oncogenic actions through stimulating the beta-catenin/T cell factor-mediated transcription, which plays critical roles in colorectal carcinogenesis.
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PMID:Prostaglandin E2 Stimulates the beta-catenin/T cell factor-dependent transcription in colon cancer. 1589 4

Cdx-2 is a transactivator for the proglucagon gene in pancreatic and intestinal endocrine cells. Cdx-2 is also expressed in differentiated intestinal epithelia of nonendocrine origin. Cdx-2-/- mice are embryonic lethal, while Cdx-2+/- mutants show multiple malfunctions including the formation of intestinal polyps. Within the polyps, the remaining wild type Cdx-2 allele ceases its expression, while the expression of both Cdx-2 and proglucagon in the endocrine cells remains unaltered, indicating that Cdx-2 could be haplo-insufficient for nonendocrine cells, but not for proglucagon producing endocrine cells. We propose that mechanisms underlying Cdx-2 expression and auto-regulation [Xu F, Li H & Jin T (1999), J Biol Chem274, 34310-34316] differ in these two types of cells. We show here that forskolin and cAMP upregulate Cdx-2 expression in proglucagon producing cells, but not in colon cancer cells and primary intestinal cell cultures. It is unlikely that the activation is mainly mediated by PKA, because the activation was observed in a PKA deficient cell line. Co-transfecting a dominant negative Ras expression plasmid substantially repressed the Cdx-2 promoter, in contrast to a previous finding that Ras is a negative factor for Cdx-2 expression in colon cancer cells. Furthermore, forskolin activated ERK1/2 phosphorylation in the endocrine cells, and attenuation of ERK1/2 phosphorylation by its inhibitor is associated with attenuated Cdx-2 expression. Finally, an Epac pathway specific cAMP analogue stimulated both ERK1/2 phosphorylation and Cdx-2 expression. Taken together, our observations suggest that Cdx-2 expression is regulated by the second messenger cAMP, cell-type specifically, via the Epac pathway.
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PMID:PKA independent and cell type specific activation of the expression of caudal homeobox gene Cdx-2 by cyclic AMP. 1594 9


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