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)

Mutations in a protein phosphatase and a protein kinase cause hamartomatous polyposis syndromes, which are characterised by the formation of multiple benign polyps and an increased susceptibility to some types of cancer.
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PMID:Cancer predisposition: where's the phosphate? 954 92

LKB1 Serine/Threonine (ST) kinase (also called STK11) originally identified in our novel protein kinase search project has recently been recognized as a susceptibility gene of Peutz-Jeghers Syndrome (PJS; MIM 175200). PJS is a dominantly inherited human disorder which is characterized by gastrointestinal hamartomatous polyposis and mucocutaneous melanin pigmentation. Since PJS patients also show a predisposition to a wide spectrum of cancers, it is speculated that LKB1 has a tumor suppressor function. In the present study we have characterized the basic biochemical property of LKB1. In the analysis of mutant LKB1 identified in PJS patients, it was found that one of the mutants, SL26, does not lose its kinase function, but alters its subcellular distribution to accumulate in the nucleus only, whereas wild type LKB1 shows both nuclear and cytoplasmic localization. Domain mapping of the nuclear targeting signal of LKB1 assigned it to its amino terminal side. Furthermore, it was shown that LKB1 also has a cytoplasmic retention ability which is considered defective and pathogenic in the SL26 mutant. It is speculated that subcellular distribution of LKB1 is regulated in the balance of these two forces, importation into the nucleus and retention within the cytoplasm; and the cytoplasmic retention ability is necessary for LKB1 to fulfil its normal function.
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PMID:Loss of cytoplasmic retention ability of mutant LKB1 found in Peutz-Jeghers syndrome patients. 1044 97

The increased level of cytoplasmic beta-catenin through the mutations to either beta-catenin or adenomatous polyposis coli (APC) has been proposed as an important oncogenic step in various tumors. Gastric cancer showed frequent genetic alterations of the APC gene, and the risk for gastric cancer in familial adenomatosus polyposis patients is 10 times higher than that in the general population. These findings raise the possibility that mutations of beta-catenin may also be associated with the development of gastric cancer. We detected seven somatic mutations in a portion of exon 3 encoding for the glycogen synthase kinase 3beta phosphorylation consensus region of the beta-catenin gene in 43 gastric cancers. All of these mutations were missense mutations, of which five are in the highly conserved aspartic acid 32 and two are in serine 29; all of these seven mutations were detected exclusively in intestinal-type gastric cancers (7 of 26; 26.9%), but not in the diffuse-type (0 of 17). We concluded that disruption of the APC/beta-catenin/T cell factor-lymphoid enhancer binding factor pathway might play an important role especially in the development of intestinal-type gastric cancer.
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PMID:Frequent somatic mutations of the beta-catenin gene in intestinal-type gastric cancer. 1048 68

The wnt pathway regulates the steady state level of beta-catenin, a transcriptional coactivator for the Tcf3/Lef1 family of DNA binding proteins. We demonstrate that Tcf3 can inhibit beta-catenin turnover via its competition with axin and adenomatous polyposis for beta-catenin binding. A mutant of beta-catenin that cannot bind Tcf3 is degraded faster than the wild-type protein in Xenopus embryos and extracts. A fragment of beta-catenin and a peptide encoding the NH2 terminus of Tcf4 that block the interaction between beta-catenin and Tcf3 stimulate beta-catenin degradation, indicating this interaction normally plays an important role in regulating beta-catenin turnover. Tcf3 is a substrate for both glycogen synthase kinase (GSK) 3 and casein kinase (CK) 1epsilon, and phosphorylation of Tcf3 by CKIepsilon stimulates its binding to beta-catenin, an effect reversed by GSK3. Tcf3 synergizes with CK1epsilon to inhibit beta-catenin degradation, whereas CKI-7, an inhibitor of CK1epsilon, reduces the inhibitory effect of Tcf3. Finally, we provide evidence that CK1epsilon stimulates the binding of dishevelled (dsh) to GSk3 binding protein (GBP) in extracts. Along with evidence that a significant amount of Tcf protein is nonnuclear, these findings suggest that CK1epsilon can modulate wnt signaling in vivo by regulating both the beta-catenin-Tcf3 and the GBP-dsh interfaces.
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PMID:Physiological regulation of [beta]-catenin stability by Tcf3 and CK1epsilon. 1152 35

It has been repeatedly observed that non-steroidal anti-inflammatory drugs, in particular sulindac and derivatives, may effectively prevent colorectal cancer. It has become apparent that exisulind (sulindac sulfone) induces apoptosis in tumor cells. Cell biological studies provided circumstantial evidence that the mechanism by which these agents exert their antitumor effect should be attributed to inhibition of cyclic-GMP phosphodiesterase (cGMP-PDE). The secondary increase of cGMP activates protein kinase G (PKG) and induces transcription of caspase genes, resulting in apoptosis. cGMP-PDEs comprise 11 gene families. Each family of PDEs is characterized by their ability to bind and degrade cAMP and cGMP but differs in physical and kinetic properties. Any single type of cell expresses a limited number of PDE-isoforms in order to regulate cGMP or cAMP levels. The majority of PDE inhibitors that have been investigated until now, except exisulind and a number of its analogs, do not induce apoptosis in tumor cells. Sulindac has a preventive effect on tumorigenesis in patients with polyposis of the colon. The anticancer effect of the novel sulindac derivatives has been demonstrated in over 50 different tumor cell lines, as well as in animal models of a variety of human cancers, such as mammary, prostate, lung and pancreatic carcinomas. Selective apoptotic antineoplastic drugs (SAANDs), as developed by Cell Pathways Inc, represent a novel class of anticancer agents that target a novel form of cGMP-PDE. It is believed that this enzyme is selectively increased in precancerous and cancerous cells. By specifically inhibiting the action of this particular cGMP-PDE, SAANDs enable various tumor cells to process an apoptotic signal and to commit suicide without affecting normal cells. As a result, side effects normally associated with traditional chemotherapeutic agents are not observed. One of the new compounds, CP-461, appeared < or = 100-fold more potent than exisulind in vitro. Studies of human cancer cell lines in vitro and dose-ranging phase I/II studies, both oral and iv, are discussed. Combinations of CP-461 with other chemotherapeutic agents are well tolerated.
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PMID:Sulindac and its derivatives: a novel class of anticancer agents. 1156 47

Mutations in the glycogen synthase kinase 3beta (GSK3beta) phosphorylation sites of the beta-catenin gene exon 3 are found in 20-30% of human primary hepatocellular carcinoma (HCC), whereas mutations in the APC or AXIN genes are found in other HCC populations. These data strongly suggest that the Wnt signaling pathway is involved in hepatocarcinogenesis. To determine the role of beta-catenin in intestinal tumorigenesis, we earlier constructed a mutant mouse strain Catnb(lox(ex3)), in which exon 3 of the beta-catenin gene was sandwiched by loxP sequences. By genetic crosses of these mice with the Fabpl-cre transgenic mice that express the cre gene controlled by the fatty acid binding protein gene promoter, we introduced the beta-catenin stabilizing mutation into the small intestine and liver. Although numerous polyps were formed in the small intestine, we did not find any neoplastic (i.e., dysplastic) foci in the liver, and the mice died in 5 weeks after birth because of acute liver damage accompanying mitochondrial swelling. When a recombinant adenovirus that expresses the cre gene from a human cytomegalovirus early gene promoter was constructed and inoculated at a high multiplicity (10(9) plaque-forming units/mouse), the Catnb(lox(ex3)) mice showed marked hepatomegaly, with similar mitochondrial swelling in the hepatocytes, and died within 3 weeks after infection. On the other hand, when inoculated at lower multiplicities of infection (10(7) and 10(8) plaque-forming units/mouse, respectively), the Catnb(lox(ex3)) mice survived >6 months without any neoplastic foci in the liver, although the nuclear localization of beta-catenin was found in some hepatocytes even after 6 months. These results suggest that, in contrast to intestinal polyposis, the Wnt pathway activation by stabilized beta-catenin is not sufficient for hepatocarcinogenesis, but additional mutations or epigenetic changes may be required.
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PMID:Lack of tumorigenesis in the mouse liver after adenovirus-mediated expression of a dominant stable mutant of beta-catenin. 1192 13

Wnt regulation of beta-catenin degradation is essential for development and carcinogenesis. beta-catenin degradation is initiated upon amino-terminal serine/threonine phosphorylation, which is believed to be performed by glycogen synthase kinase-3 (GSK-3) in complex with tumor suppressor proteins Axin and adnomatous polyposis coli (APC). Here we describe another Axin-associated kinase, whose phosphorylation of beta-catenin precedes and is required for subsequent GSK-3 phosphorylation of beta-catenin. This "priming" kinase is casein kinase Ialpha (CKIalpha). Depletion of CKIalpha inhibits beta-catenin phosphorylation and degradation and causes abnormal embryogenesis associated with excessive Wnt/beta-catenin signaling. Our study uncovers distinct roles and steps of beta-catenin phosphorylation, identifies CKIalpha as a component in Wnt/beta-catenin signaling, and has implications to pathogenesis/therapeutics of human cancers and diabetes.
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PMID:Control of beta-catenin phosphorylation/degradation by a dual-kinase mechanism. 1195 36

The human LKB gene (official HUGO symbol, STK11) encodes a serine/threonine protein kinase that is defective in patients with Peutz-Jeghers syndrome (PJS). PJS is an autosomal dominantly inherited syndrome characterized by hamartomatous polyposis of the gastrointestinal tract and mucocutaneous pigmentation. To date, 145 different germline LKB1 mutations have been reported. The majority of the mutations lead to a truncated protein product. One mutational hotspot has been observed. A 1-bp deletion and a 1-bp insertion at the mononucleotide repeat (C6 repeat, c.837-c.842) between the codons 279-281 have been found in six and seven unrelated PJS families, respectively. However, these mutations account only for approximately 7% of all mutations identified in the PJS families (13/193). A review of the literature provides a total of 40 different somatic LKB1 mutations in 41 sporadic tumors and seven cancer cell lines. Mutations occur particularly in lung and colorectal cancer. Most of the somatic LKB1 mutations result in truncation of the protein. A mutational hotspot seems to be a C6 repeat accounting for 12.5% of all somatic mutations (6/48). These results are concordant with the germline mutation spectrum. However, the proportion of the missense mutations seems to be higher among the somatic mutations (45%) than among the germline mutations (21%), and only seven of the mutations are exactly the same in both of the mutation types.
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PMID:Mutations in the human LKB1/STK11 gene. 1611 Apr 86

The methylation of CpG dinucleotides has become a topic of great interest in cancer research, and the methylation of promoter regions of several tumor suppressor genes has been identified as a marker of tumorigenesis. Evaluation of DNA methylation markers in tumor tissue requires hundreds of samples, which must be analyzed quantitatively due to the heterogeneous composition of biological material. Therefore novel, fast and inexpensive methods for high throughput analysis are needed. Here we introduce a new assay based on peptide nucleic acid (PNA)-library hybridization and subsequent MALDI-TOF analysis. This method is multiplexable, allows the use of standard 384 well automated pipetting, and is more specific and flexible than established methods, such as microarrays and MS-SNuPE. The approach was used to evaluate three candidate colon cancer methylation markers previously identified in a microarray study. The methylation of the genes Ade-nomatous polyposis coli (APC), glycogen synthase kinase-beta-3 (GSK3beta) and eyes absent 4 (EYA4) was analyzed in 12 colon cancer and 12 normal tissues. APC and EYA4 were confirmed as being differentially methylated in colon cancer patients whereas GSK3beta did not show differential methylation.
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PMID:Novel method for high throughput DNA methylation marker evaluation using PNA-probe library hybridization and MALDI-TOF detection. 1667 Apr 26

LKB1 encodes a serine/threonine protein kinase that is defective in patients with Peutz-Jeghers syndrome (PJS), a hereditary disorder characterized by gastrointestinal hamartomatous polyposis and an increased risk of cancer development. Although a tentative molecular classification of PJS patients was recently made according to their LKB1 mutation status, it is difficult to clarify the genotype-phenotype relationship because of the rarity and genetic heterogeneity of this disease. Here we report on two probands with PJS whose intestinal hamartomatous polyposis was treated by laparoscopyassisted polypectomy. Direct sequencing analyses revealed a nonsense mutation at codon 240 in exon 5 in one patient, and a mutation at a splicing donor site in intron 5 in the other patient. No additional somatic mutations were detected in the resected hamartomas in either case. Immunohistochemical analysis revealed an elevated expression of cyclooxygenase-2, and almost complete loss of LKB1 expression in the polyps, suggesting that a biallelic inactivation of the LKB1 gene was responsible for the hamartoma formation. Methylation-specific polymerase chain reaction analysis revealed no hypermethylation of the LKB1 promoter. Mutation analysis is useful in making a precise diagnosis of PJS in candidate probands, and may in the near future provide valuable information for predicting cancer risk based on genotype-phenotype correlations.
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PMID:Molecular insights into Peutz-Jeghers syndrome: two probands with a germline mutation of LKB1. 1860 Mar 94


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