Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0699790 (colon cancer)
 28,837 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

One of the extension proteins on the carboxy terminus of ubiquitin was reported as the ribosomal protein S27a. We have cloned a gene which encodes this ubiquitin hybrid protein from a complementary DNA library of a human colon carcinoma cell line. Northern blot analysis of surgical specimens from colon cancer patients showed that these messenger RNA levels were higher in tumor tissue than in adjacent normal mucosa. Furthermore, to investigate the role of this novel ubiquitin hybrid gene in cellular growth control, the responsiveness of this gene to serum growth factors was examined. Within 30 min after serum or 12-O-tetradecanoylphorbol-13-acetate stimulation, its messenger RNA expression in rat fibroblast cells (Rat 1) was increased. Nuclear runoff transcription studies showed that the kinetics of induction of this gene is almost identical to that of protooncogene c-jun or c-fos, the known early growth response genes. Thus, this ubiquitin hybrid gene appears to be a novel early growth response gene overexpressed in human colon cancer and warrants further studies in the pathogenesis of colorectal carcinoma.
 ...
PMID:Ubiquitin-ribosomal protein S27a gene overexpressed in human colorectal carcinoma is an early growth response gene. 838 74

A cDNA clone (AF3) encoding the ubiquitin A gene 52 amino acid extension fusion protein (UbA52) was isolated from a subtracted cDNA library of human colorectal carcinoma minus adjacent normal mucosa. In Northern hybridization the mRNA signal for UbA52 was greater in surgical samples of colonic carcinoma (T) than in paired adjacent normal (N) tissues in 24 of 29 cases (T/N = 3.4 +/- 0.5, P < 0.01). An oligonucleotide probe specific for only the 52 amino acid extension confirmed the overexpression of UbA52. In contrast, there was no overexpression of UbA52 mRNA in gastric cancer samples (n = 7, T/N = 1.0 +/- 0.3). The mRNA of several ribosomal proteins, and of another ubiquitin A gene fusion protein, UbA80, with an 80 amino acid extension of ribosomal protein S27a, have been reported to be over-expressed in colon cancer, but not as yet at the protein level. Using rabbit antisera to the ribosomal protein component S27a we demonstrate over-expression of S27a at the protein level in colonic (n = 5), but not gastric (n = 6) carcinomas. Therefore it is likely that both UbA80 and UbA52 are overexpressed in colon cancer, but not in gastric cancer.
 ...
PMID:Ubiquitin fusion proteins are overexpressed in colon cancer but not in gastric cancer. 854 45

Signaling by members of the Src family of protein tyrosine kinases, such as Src and Fyn, is important in many biological responses, including gene transcription, cell-cycle progression, and cell adhesion and spreading [1] [2]. Unregulated Src kinase activity has been implicated in the progression of colon cancer and transformation of cultured cells [3] [4] [5] [6]. Thus, precise regulation of Src activity is critical for normal cell growth. Src kinase activity is downregulated by the carboxy-terminal Src kinase (Csk), a tyrosine kinase that phosphorylates a conserved tyrosine residue in the carboxy-terminal tail of Src [7] [8]. When phosphorylated, this tyrosine residue mediates an intramolecular interaction that results in a 'closed' or inactive conformation [1] [2] [9] [10]. Here, we report that loss of csk resulted in a reduction in the abundance of the Src and Fyn proteins, which could be restored by reintroducing catalytically active Csk. The effect of Csk on Src expression was not due to an increase in Src message, but to stabilization of the Src protein. Inhibition of proteasome activity also increased the level of Src protein in csk-deficient cells. Src was found to be ubiquitinated, and activation of Src increased the extent of polyubiquitination. Thus, ubiquitin-proteasome-dependent degradation represents an additional mechanism by which active Src can be downregulated.
 ...
PMID:Ubiquitin-dependent degradation of active Src. 1050 17

Cyclooxygenase-2 (COX-2) is not normally expressed in the human large intestine, but its levels are increased in the majority of human colorectal carcinomas. Here we investigate the regulation of constitutive COX-2 expression and prostaglandin production in human colorectal carcinoma cells. Both COX-2 mRNA and protein were expressed in well differentiated HCA-7, Moser, LS-174, and HT-29 cells, albeit at different levels. COX-2 expression was not detected in several poorly differentiated colon cancer cell lines including DLD-1. Transcriptional regulation played a key role for the expression of COX-2 in human colon carcinoma cells, and both the nuclear factor for interleukin-6 regulatory element and the cAMP-response element were responsible for regulation of COX-2 transcription. COX-2 mRNA was more stable in HCA-7 cells than in the other cell lines tested. Both transcriptional and post-transcriptional regulation of COX-2 involved the MAP kinase pathway. Modulation of the Akt/protein kinase B or Rho B signaling pathways altered the levels of COX-2 expression. Furthermore, COX-2 protein is degraded through ubiquitin proteolysis, and its half-life was approximately 3.5-8 h. HCA-7 cells produced significant quantities of prostaglandin E(2) and other prostaglandins. Moser and LS-174 cells also generated prostaglandins, but levels were significantly lower than that observed in HCA-7 cells.
 ...
PMID:Regulation of constitutive cyclooxygenase-2 expression in colon carcinoma cells. 1093 Apr 1

A bicyclic hexapeptide, RA-VII or O-methyl deoxybouvardin, isolated from Rubia cordifolia, is known to inhibit protein biosynthesis in vitro and in vivo. We here demonstrate that the treatment of human colon cancer DLD-1 cells with RA-VII induces cell growth inhibition associated with a partial G1 arrest and a rapid decrease (below 2 h) in the level of cyclin D1 protein. Since cycloheximide, another protein synthesis inhibitor, neither decreased the amount of cyclin D1 in the cells nor arrested cells in G1 phase, it is unlikely that this RA-VII-induced reduction of cyclin D1 was fully dependent on its direct inhibitory effect of protein synthesis. Northern blot analysis revealed that RA-VII did not affect the level of cyclin D1 mRNA. Meanwhile, pre-treatment of cells with lactacystin, a proteasome inhibitor, abolished the RA-VII-induced decrease in cyclin D1. Moreover, RA-VII still decreased cyclin D1 protein in the presence of cycloheximide. These results indicate that the RA-VII-induced cyclin D1 decrease depends on cyclin D1 degradation via the ubiquitin-proteasome pathway and does not require additional protein synthesis. RA-VII might actively proceed the degradation process of cyclin D1 via the ubiquitin-proteasome pathway in DLD-1 cells.
 ...
PMID:Antitumor bicyclic hexapeptide RA-VII modulates cyclin D1 protein level. 1139 71

As a single agent, gemcitabine (2',2'-difluorodeoxycytidine) has shown minimal activity against gastrointestinal malignancies with only a modest improvement in survival in patients with pancreatic cancer. Recently, gemcitabine resistance has been associated with the up-regulation of mRNA and protein levels of the ribonucleotide reductase M2 subunit (RR-M2), a rate-limiting enzyme in DNA synthesis that is cell cycle regulated. In this study we show that flavopiridol, a cyclin-dependent kinase inhibitor, enhances the induction of apoptosis by gemcitabine in human pancreatic, gastric, and colon cancer cell lines. As determined by quantitative fluorescence microscopy, flavopiridol enhanced gemcitabine-induced apoptosis 10-15-fold in all of the cell lines tested in a sequence-dependent manner. This was confirmed by poly(ADP-ribose) polymerase cleavage and mitochondrial cytochrome c release. Colony formation assays confirmed the apoptotic rates, showing complete suppression of colony formation only after exposure to sequential treatment of G(24)-->F(24). This is associated with suppression of the RR-M2 protein. This appears to be related to down-regulation of E2F-1, a transcription factor that regulates RR-M2 transcription and hypophosphorylation of pRb. The proteasome inhibitor PS-341 could restore the protein levels of E2F-1 in G(24)-->F(24) treatment indicating that E2F-1 down-regulation is attributable to its increased degradation via ubiquitin-proteasome pathway. This also resulted in restoration of RR-M2 mRNA and protein. These results indicate that flavopiridol in gemcitabine-treated cells inhibits parts of the machinery necessary for the transcription induction of RR-M2. Thus, combining flavopiridol with gemcitabine may provide an important and novel new means of enhancing the efficacy of gemcitabine in the treatment of gastrointestinal cancers.
 ...
PMID:Flavopiridol increases sensitization to gemcitabine in human gastrointestinal cancer cell lines and correlates with down-regulation of ribonucleotide reductase M2 subunit. 1148 36

Apoptosis is a morphologically distinct form of programmed cell death that plays a major role in cancer treatments. This cellular suicide program is known to be regulated by many different signals from both intracellular and extracellular stimuli. Here we report that p53 suppressed expression of the cellular FLICE-inhibitory protein (FLIP) that potentially blocks apoptotic signaling in human colon cancer cell lines expressing mutated and wild-type p53. In contrast, the expression of the death receptor KILLER/DR5 (TRAIL-R2) had no effect on FLIP expression, although exogenous p53 is known to induce KILLER/DR5 expression. In line with these observations, FLIP-negative cancer cells were sensitive to both p53- and KILLER/DR5-mediated apoptosis, whereas cells containing high levels of FLIP underwent apoptotic cell death when triggered by ectopic p53 expression but not by KILLER/DR5 expression. Treating the cells with a specific inhibitor of the proteasome inhibited the decrease of FLIP by p53, suggesting that p53 enhances the degradation of FLIP via a ubiquitin-proteasome pathway. Thus, the data indicate that p53-mediated downregulation of FLIP may explain the potent sensitization of human cancer cells to the apoptotic suicide program induced by wild-type p53 gene transfer.
 ...
PMID:Accelerated degradation of cellular FLIP protein through the ubiquitin-proteasome pathway in p53-mediated apoptosis of human cancer cells. 1152 13

Exisulind and its analogues are inhibitors of cyclic GMP phosphodiesterases (PDEs) that have been shown to activate and induce protein kinase G, resulting in the induction of apoptosis in colon cancer cells. These drugs also reduce beta-catenin protein levels and decrease cyclin D1 mRNA levels in SW480 cells. Herein we report on studies pertaining to exisulind regulation of beta-catenin levels and activity in colon tumor cells. Exisulind and its higher-affinity PDE analogues, (Z)-5-fluoro-2-methyl-(4-pyridylidene)-3-(N-benzyl)-indenylacetamide hydrochloride (CP461) and (Z)-1H-indene-3-acetamide, 5-fluoro-2-methyl-N-(phenylmethyl)-1-[(3,4,5-trimethoxyphenyl)methylene] (CP248), reduced beta-catenin, including the nuclear beta-catenin in SW480 cells (EC(50) approximately 200 microM, 1 microM, and <1 microM, respectively). The 50% reduction of beta-catenin was seen in 8-14 hr. There was no change in beta-catenin mRNA. Exisulind-induced beta-catenin reduction was blocked by the proteasomal inhibitor MG132 (Z-leu-Leu-Leu-CHO), indicating that the effect of exisulind involved ubiquitin-proteasomal degradation. A consequence of reduced beta-catenin in SW480 cells was that exisulind, CP461, and CP248 caused a concentration- and time-dependent decrease in cyclin D1 levels (EC(50) approximately 300 microM, 1 microM, and <1 microM, respectively) in 4 hr. The effect was via decreased cyclin D1 mRNA levels. Exisulind-induced degradation of beta-catenin was not blocked by the inhibition of caspase-3 activity and/or apoptosis, and some SW480 cells showed a reduction in beta-catenin levels before the appearance of early apoptosis indicators. Expression of the N-terminal 170 amino acid fragment of beta-catenin reduced the effects of beta-catenin degradation, cyclin D1 reduction, and the apoptosis response to exisulind. These results indicate that exisulind-induced beta-catenin degradation precedes the induction of apoptosis and that the down-regulation of inappropriate beta-catenin-activated genes accounts in part for the pro-apoptotic effects of exisulind and CP461 in colon tumor cells.
 ...
PMID:Pro-apoptotic actions of exisulind and CP461 in SW480 colon tumor cells involve beta-catenin and cyclin D1 down-regulation. 1239 15

Constitutive activation of the Wnt/beta-catenin pathway is thought to play a central role in colorectal carcinogenesis. A key output in this pathway is the nuclear level of beta-catenin, which determines the transcription of T-cell transcription factor (TCF)/lymphoid enhancer-binding factor-responsive target genes. In unstimulated cells, beta-catenin is continuously targeted for ubiquitin-dependent degradation, which depends on its NH(2)-terminal phosphorylation by glycogen synthase kinase-3beta (GSK-3beta) in association with a multiprotein complex. Previously, we have shown that the nonsteroidal anti-inflammatory drugs (NSAIDs) aspirin and indomethacin down-regulate beta-catenin/TCF signaling in colorectal cancer cells. Here, we demonstrate that the reduced signaling activity of beta-catenin in response to NSAIDs is a result of its enhanced phosphorylation. In SW948 and SW480 colorectal cancer cells, phosphorylation of NH(2)-terminal S/T residues time dependently increased in response to aspirin and indomethacin. In contrast, in 293 cells, NSAID treatment failed to induce detectable levels of beta-catenin phosphorylation but resulted in degradation of beta-catenin within 24 h in serum-deprived cells. The aspirin-induced beta-catenin phosphorylation in colon cancer cells preceded down-regulation of beta-catenin/TCF signaling, suggesting a causal relationship. Inhibition of this process by LiCl pointed to participation of GSK-3beta. Unexpectedly, GSK-3beta was also phosphorylated upon aspirin treatment in six colorectal cancer cell lines. We present evidence that inactivation of a phosphatase rather than stimulation of a kinase or interference with the ubiquitination machinery may be the cause of the stabilized phosphorylation. The data emphasize the importance of beta-catenin in the pathogenesis of colorectal cancer and define it as a key target for anticancer therapeutics.
 ...
PMID:Reduction of beta-catenin/T-cell transcription factor signaling by aspirin and indomethacin is caused by an increased stabilization of phosphorylated beta-catenin. 1281 29

The impact that modern molecular biology has had on elucidating the genetic basis of neoplasia is best illustrated by the paradigm of sporadic and hereditary colon cancer. The clinical and hereditary picture of the familial adenomatous polyposis syndrome (FAP) implied the existence of a single gene that regulates the formation of adenomatous polyps, the precursor for most colorectal cancers. The identification of an interstitial deletion on chromosome 5q in a patient with Gardner's variant of FAP combined with classic linkage analysis facilitated the positional cloning of the adenomatous polyposis coli (APC) gene in 1991. FAP is caused by germline mutations in the APC gene. Somatic mutations in the APC gene are an early event in colorectal tumorigenesis, and can be detected in the majority of colorectal tumors. APC consists of 8,535 bp spanning 21 exons (16 translated exons) and encodes a 2,861 amino acid protein that is expressed in specific epithelial and mesenchymal cells of several fetal and adult human tissues. The APC protein is a large multidomain protein with a molecular mass of 300 kD. The best-known function of the APC protein is the Wnt-1 signaling pathway. Binding Wnt to its receptor, frizzled), leads to the inactivation of the glycogen synthase kinase 3 beta in a cytoplasmic complex with APC, beta-catenin, axin and components of the ubiquitin ligation machinery. This leads to a decrease in beta-catenin phosphorylation and inhibits its proteasomal degradation. As a consequence, increased beta-catenin is available to bind transcription factors leading to the activation of proliferative genes. In addition, APC has recently emerged as a multifunctional protein that can affect a variety of fundamental cellular processes, in particular cytoskeletal regulation and chromosomal stability. Improved understanding of both the genetics and biology of APC may, in time, culminate in preventive or therapeutic strategies specifically targeted at reducing the burden of colorectal cancer.
 ...
PMID:[Familial adenomatous polyposis syndrome (FAP): pathogenesis and molecular mechanisms]. 1468 80


1 2 3 4 5 6 7 8 9 10 Next >>