Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Myristoylation refers to the co-translational addition of a myristoyl group to an amino-terminal glycine residue of a protein by an ubiquitously distributed enzyme myristoyl-CoA:protein N-myristoyltransferase (NMT, EC 2.3.1.97). This review describes the basic enzymology, molecular cloning and regulation of NMT activity in various pathophysiological processes such as colon cancer and diabetes.
Mol Cell Biochem 2000 Jan
PMID:N-myristoyltransferase. 1071 34

Epidemiologic observations and laboratory research have suggested that dietary selenium reduces the risk of colon cancer. Selenium-enriched brewer's yeast as a dietary supplement reduces the incidence of and mortality from cancer of the colon in humans. It is not clear whether the observed inhibitory effect is due to selenomethionine, or to other forms of selenium, or to a mixture of the selenium compounds present in selenium-enriched brewer's yeast. Therefore, bioassay described in this study examined the chemopreventive efficacy of 10 and 15 ppm selenomethionine, equivalent to 3.6 and 5.4 ppm as selenium, against azoxymethane (AOM)-induced colon carcinogenesis. At five weeks of age, groups of male F344 rats were fed diets containing 0 (control diet), 10 or 15 ppm selenomethionine. At seven and eight weeks of age, all rats except those in vehicle-treated groups received s.c. injections of AOM at a dose rate of 15 mg/kg body wt. The rats were maintained on their respective diets for 52 weeks and were then sacrificed. Colon tumors were processed and evaluated histopathologically. Colon tumor incidence and multiplicity were analyzed statistically. No obvious toxic effects were observed following dietary administration of 10 or 15 ppm selenomethionine as indicated by body weight gain. Administration of 10 or 15 ppm selenomethionine had no significant effect on colon tumor incidence and multiplicity. This study suggests that i) selenomethionine lacks chemopreventive efficacy against AOM-induced colon carcinogenesis and ii) other forms of selenium or a mixture of selenium compounds present in selenium-enriched brewer's yeast need to be evaluated for their chemopreventive efficacy.
Int J Mol Med 2000 Apr
PMID:Lack of chemopreventive efficacy of DL-selenomethionine in colon carcinogenesis. 1071 45

Our purpose was to analyze whether postmitotic Caco-2 colon cancer cells, although they express most of the differentiation characteristics of terminally differentiated intestinal epithelial cells, still maintain, unlike normal cells, a proliferation potential. Experiments were performed with clone TC7 of the Caco-2 cell line. Dividing TC7 cells are undifferentiated and express detectable levels of thymidylate synthase (TS) and cytochrome P450 1A1 (CYP1A1) mRNAs. When reaching confluence TS and CYP1A1 are downregulated, mitosis is no longer detectable, and differentiation takes place, as demonstrated by appearance and increasing levels of differentiation-associated marker mRNAs (e.g., sucrase-isomaltase (SI), dipeptidylpeptidase-IV (DPP-IV) or GLUT5), increasing activities of sucrase and DPP-IV, and increasing expression, on immunofluorescence analysis, of SI on the surface of the cell layer. Trypsinization and seeding of late postconfluent cells (day 30) expressing complete differentiation results within 24 h in upregulation of TS and CYP1A1, a concomitant and dramatic disappearance of differentiation marker mRNAs associated with a decrease in sucrase and DPP-IV activities, and delayed resumption of cell division. This is followed, after the cells have reached confluence again, by downregulation of TS and CYP1A1 and resumption of cell differentiation. The ability of differentiated cells to dedifferentiate was further confirmed by wounding the cell layer of late postconfluent differentiated cultures: within 24 h following the wound, cells migrate from the wound edge and dedifferentiate, as demonstrated by transmission electron microscopy and disappearance of SI from the cell surface of migrating cells. Late postconfluent differentiated cells were tumorigenic in nude mice. These results raise the question of the validity of the concept of differentiation therapy when applied to colon cancer cells.
Exp Mol Pathol 2000 Aug
PMID:Postmitotic differentiation of colon carcinoma caco-2 cells does not prevent reentry in the cell cycle and tumorigenicity. 1089 Dec 91

Coiled coils serve as dimerization domains for a wide variety of proteins, including the medically important oligomeric tumor suppressor protein, APC. Mutations in the APC gene are associated with an inherited susceptibility to colon cancer and with approximately 75 % of sporadic colorectal tumors. To define the basis for APC pairing and to explore the anatomy of dimeric coiled coils, we determined the 2.4 A resolution X-ray crystal structure of the N-terminal dimerization domain of APC. The peptide APC-55, encompassing the heptad repeats in APC residues 2-55, primarily forms an alpha-helical, coiled-coil dimer with newly observed core packing features. Correlated asymmetric packing of four core residues in distinct, standard rotamers is associated with a small shift in the helix register. At the C terminus, the helices splay apart and interact with a symmetry-related dimer in the crystal to form a short, anti-parallel, four-helix bundle. N-terminal fraying and C-terminal splaying of the helices, as well as the asymmetry and helix register shift describe unprecedented dynamic excursions of coiled coils. The low stability of APC-55 and divergence from the expected coiled-coil fold support the suggestion that the APC dimerization domain may extend beyond the first 55 residues.
J Mol Biol 2000 Aug 04
PMID:Crystal structure of the amino-terminal coiled-coil domain of the APC tumor suppressor. 1092 98

The cell surface decoy receptor proteins TRID (also known as DcR1 or TRAIL-R3) and TRUNDD (DcR2, TRAIL-R4) inhibit caspase-dependent cell death induced by the cytotoxic ligand TRAIL in part because of their absent or truncated cytoplasmic death domains, respectively. We previously identified the death domain containing proapoptotic TRAIL death receptor KILLER/DR5 (TRAIL-R2) as an upregulated transcript following exposure of cancer cells, with wild-type but not with mutant or degraded p53 proteins, to a cytotoxic dose of adriamycin. In the present studies we provide evidence that expression of the TRAIL decoy receptors TRUNDD and TRID increases following infection of cancer cells with p53-expressing adenovirus (Ad-p53), in a manner similar to other p53 target genes such as KILLER/DR5 and p21WAF1/CIP1. Subsequent overexpression of TRUNDD in colon cancer cell lines caused a significant delay in killing induced by TRAIL. Furthermore, cotransfection of TRUNDD with either p53 or KILLER/DR5 (at a 4:1 DNA ratio) in colon cancer cells decreased cell death caused by either gene. This protective effect of TRUNDD was not dependent on the presence of TRAIL, and overexpression of TRUNDD did not alter the protein levels of either p53 or KILLER/ DR5. Further deletion studies showed that whereas protection by TRUNDD against TRAIL-mediated apoptosis did not require an intact intracellular domain (ICD), the first 43 amino acids of the ICD of TRUNDD were needed for protection against cell death induced by p53 or KILLER/DR5. Our results suggest a model in which the TRAIL decoy receptors may be induced by p53, thereby attenuating an apoptotic response that appears to involve KILLER/DR5. Therefore, the p53-dependent induction of TRUNDD may provide a mechanism to transiently favor cell survival over cell death, and overexpression of TRUNDD may be another mechanism of escape from p53-mediated apoptosis in gene therapy experiments.
Mol Ther 2000 Feb
PMID:The TRAIL decoy receptor TRUNDD (DcR2, TRAIL-R4) is induced by adenovirus-p53 overexpression and can delay TRAIL-, p53-, and KILLER/DR5-dependent colon cancer apoptosis. 1093 23

Gastrin-releasing peptide (GRP) is a mitogen and morphogen important in the development of human colon cancers. Although epithelial cells lining the colon do not normally express GRP or its receptor (GRP-R), most human tumors express GRP-R mRNA. Yet functional protein has only been detected in 24 to 40% of colon cancers. To elucidate the reason for the difference between the expression of GRP/GRP-R mRNA and protein, we studied nine human colon cancer cell lines. Quantitative polymerase chain reaction revealed that all colon cancer cell lines expressed similar amounts of mRNA for both GRP as well as GRP-R. Yet binding studies using (125)I-Tyr(4)-bombesin detected functional receptors on only five of the nine cell lines studied. Conformational fragment-length polymorphism analysis indicated that although mRNA for the ligand GRP was never mutated, mRNA for the GRP-R was always mutated. Sequencing revealed that the message for GRP-R contained between two and seven separate mutations at the nucleotide level. This resulted in 14 separate coding mutations, 2 of which were observed in more than one cell line. Each mutation was individually recreated by site-directed mutagenesis and studied in transiently transfected Chinese hamster ovary-K1 cells. Alteration of Pro(145) into a tyrosine, of Val(317) into a glutamic acid, and insertion of a 32-nucleotide segment resulting in a frameshift distal to Asp(137) all resulted in GRP receptors incapable of binding ligand. Thus, these data indicate that human colon cancers commonly express GRP and GRP-R mRNA but that receptor mutations account for the failure of functional protein to be generated.
Mol Pharmacol 2000 Sep
PMID:Characterization of gastrin-releasing peptide and its receptor aberrantly expressed by human colon cancer cell lines. 1095 54

We have previously reported that down-regulation of Cdx1 and Cdx2 mRNA expression is associated with colon carcinogenesis, and that coordinated reexpression of these genes in the HT29 colon cancer-derived cell line leads to a reduced malignant phenotype. Here we show that restoring Cdx1 and Cdx2 expression in HT29 cells enhanced the antigen presentation system, as reflected by a strong induction of the concentration of HLA-I molecules at the cell surface, resulting from increased expression of the HLA-I mRNA. Expression of the LMP2 proteasomal protein was also strongly induced by Cdx1 and Cdx2 at the transcriptional level, whereas TAP1 expression which is under the control of the same bidirectional promoter as LMP2 remained unchanged. Furthermore, expression of the adhesion molecule ICAM-1, which works in concert with HLA-I, and of the cell death promoter Fas was also increased upon Cdx1 and Cdx2 expression. Taken together, these results suggest that loss of Cdx1 and Cdx2 expression during colorectal carcinogenesis could favor the escape of tumor cells from the immune system. In conclusion, restoration of Cdx1 and Cdx2 expression should be considered in immunotherapeutic strategies for colorectal cancer.
Mol Cell Biol Res Commun 2000 May
PMID:Overexpression of Cdx1 and Cdx2 homeogenes enhances expression of the HLA-I in HT-29 cells. 1096 50

In Saccharomyces cerevisiae, positioning of the mitotic spindle depends on the interaction of cytoplasmic microtubules with the cell cortex. In this process, cortical Kar9p in the bud acts as a link between the actin and microtubule cytoskeletons. To identify Kar9p-interacting proteins, a two-hybrid screen was conducted with the use of full-length Kar9p as bait, and three genes were identified: BIM1, STU2, and KAR9 itself. STU2 encodes a component of the spindle pole body. Bim1p is the yeast homologue of the human microtubule-binding protein EB1, which is a binding partner to the adenomatous polyposis coli protein involved in colon cancer. Eighty-nine amino acids within the third quarter of Bim1p was sufficient to confer interaction with Kar9p. The two-hybrid interactions were confirmed with the use of coimmunoprecipitation experiments. Genetic analysis placed Bim1p in the Kar9p pathway for nuclear migration. Bim1p was not required for Kar9p's cortical or spindle pole body localization. However, deletion of BIM1 eliminated Kar9p localization along cytoplasmic microtubules. Furthermore, in the bim1 mutants, the cytoplasmic microtubules no longer intersected the cortical dot of Green Fluorescent Protein-Kar9p. These experiments demonstrate that the interaction of cytoplasmic microtubules with the Kar9p cortical attachment site requires the microtubule-binding protein Bim1p.
Mol Biol Cell 2000 Sep
PMID:Bim1p/Yeb1p mediates the Kar9p-dependent cortical attachment of cytoplasmic microtubules. 1098 92

The transcription factor nuclear factor-kappaB (NF-kappaB) regulates genes that can influence cell proliferation, apoptosis, and inflammatory responses. Since these events can contribute to carcinogenesis, we examined the expression of NF-kappaB inhibitory proteins (IkappaBs) in normal and transformed colonic epithelial cells. Immunohistochemical analysis of the mouse colon revealed a high level of IkappaBbeta expression in epithelial cells relative to the rest of the tissue, whereas IkappaBalpha was found primarily in cells of the lamina propria. Mouse colon tumors showed a similar cell-specific staining pattern. Immunoblot analysis of IkappaBbeta from mouse colonocytes and the human HT-29 colon cancer cell line indicated that most of the IkappaBbeta in these cells was similar to the C-terminal-truncated IkappaBbeta2 isoform. Cell fractionation studies were consistent with IkappaBbeta being a major regulator of p65-p50 NF-kappaB complexes in HT-29 cells. Interestingly, two larger proteins specifically recognized by IkappaBbeta antibodies (p106 and p112) were found in HT-29 cells and in colon tissue of carcinogen-exposed mice. The p106 and p112 proteins bound to NF-kappaB, and their levels changed during the transient interleukin-1beta activation of NF-kappaB in HT-29 cells. Evidence was obtained indicating that p106 and p112 are stably ubiquitinated forms of IkappaBbeta. We propose that deficiencies in the proteasomal degradation of IkappaBbeta lead to p106 and p112 accumulation, which in turn alter NF-kappaB regulation in colon cancer cells.
Mol Carcinog 2000 Sep
PMID:IkappaBbeta-related proteins in normal and transformed colonic epithelial cells. 1102 Feb 44

Progression of cells through the G1 phase of the cell cycle requires the assembly and activation of specific cyclin:cyclin-dependent kinase (cdk) complexes in a tightly regulated, sequential fashion. To more clearly define the temporal events leading to the G1/S transition, sequential changes in the expression of cyclin E and cdks 2, 4, and 6, as well as the phosphorylation of the retinoblastoma protein (pRb), were assayed in RA28 cells, a variant of human colon cancer RKO cells which were modified by transfection of an ecdysone-inducible antisense (AS) CD1 expression system. Induction of cyclin D1 antisense mRNA by the ecdysteroid, ponasterone A, resulted in a 55% decrease in cyclin D1 mRNA and a 58% decrease in CD1 protein levels. There was a 2.4-fold decrease in the ratio of hyperphosphorylated pRb (ppRb) to hypophosphorylated pRb, as well as a 60-75% decrease in cdk 2- and cdk 4-specific phosphorylated pRb proteins. Of interest, cyclin E-dependent phosphorylation (cdk2) decreased 2.5-fold at 3 h despite only a 30% decrease in cyclin E protein level. Levels of cdk 2, cdk 4, and cdk 6 decreased 40-70%, while levels of cyclin A and B were unaffected by induction of CD1 antisense. Induction of a CD1 antisense gene in a human colon cancer cell line resulted in rapid, concomitant changes in CD1 mRNA and protein, cyclin E, cdk2, cdk4, and cdk6, as well as the ratio of ppRb to pRb. In this system, growth regulatory events are tightly regulated and the perturbed expression of a single protein, CD1, rapidly alters expression of multiple regulatory proteins involved in the G1/S transition phase of cell cycle progression.
Mol Cell Biol Res Commun 2000 Jun
PMID:Downregulation of cyclin D1 alters cdk 4- and cdk 2-specific phosphorylation of retinoblastoma protein. 1103 57


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