Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

betaTRCP1 and betaTRCP2, components of the beta-catenin-ubiquitin ligase complex, are negative regulators of the WNT signaling pathway. We have previously isolated the betaTRCP2 gene, and detected betaTRCP2 in all gastric cancer cell lines examined. Here, expression profiles of betaTRCP1 and betaTRCP2 in various normal tissues and in primary gastric cancer were investigated. betaTRCP1 was predominant in small intestine, while betaTRCP2 was predominant in stomach. betaTRCP1 was expressed in gastric cancer cell lines MKN28, MKN45, MKN74, and KATO-III, but not in any cases of primary gastric cancer. betaTRCP2 was expressed in most cases of primary gastric cancer at almost the equal level in tumor and in non-cancerous portion of gastric mucosa. As betaTRCP2 was found to be the major betaTRCP expressed in gastric cancer, genetic alterations of betaTRCP2 in 7 gastric cancer cell lines and 12 cases of primary gastric cancer were investigated. A nucleotide substitution (Tright curved arrow C) at the nucleotide position 1486 of betaTRCP2 was identified in OKAJIMA cells, which lead to F462S amino acid substitution in the seventh WD-repeat domain. F462 was conserved among betaTRCPs derived from human, mouse, Xenopus laevis, and Drosophila melanogaster. As WD-repeats of betaTRCPs are the substrate-recognition motif of the beta-catenin-ubiquitin ligase, F462S amino-acid substitution might lead to beta-catenin stabilization, and might be implicated in carcinogenesis through activation of the WNT signaling pathway. This is the first report on comprehensive expression analyses of betaTRCP1 and betaTRCP2, and also on mutation analysis of betaTRCP2.
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PMID:Expression profiles of betaTRCP1 and betaTRCP2, and mutation analysis of betaTRCP2 in gastric cancer. 1129 41

NF-kappaB transcription factor is activated upon ubiquitination and subsequent proteolysis of its inhibitor IkappaB. The phosphorylation-dependent ubiquitination is mediated by SCF E3 ubiquitin ligase. In this study, we identified a novel murine F-box/WD40 repeat-containing protein, mHOS (a homologue of HOS/betaTrCP2). mHOS efficiently binds Skp1 protein (a 'core' component of SCF ubiquitin ligase), and phosphorylated IkappaB(alpha). We found that mHOS associates with SCF-ROC1 E3 ubiquitin ligase activity. We have also observed that mHOS is overexpressed in chemically-induced mouse skin tumors, and its overexpression (but not accelerated IkappaB phosphorylation) coincides with the accelerated degradation of IkappaB in vivo. The role of mHOS in the constitutive activation of NF-kappaB in skin carcinogenesis is discussed.
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PMID:Mouse homologue of HOS (mHOS) is overexpressed in skin tumors and implicated in constitutive activation of NF-kappaB. 1189 78

O(6)-Alkylguanine-DNA alkyltransferase (AGT) is a DNA repair protein that removes alkyl groups from DNA by transferring them to an internal Cys-145 residue. As the S-alkylcysteine is not converted back to cysteine, the protein can only act once and the resulting alkylated AGT molecule is rapidly degraded. The mechanism underlying the disappearance of the alkylated AGT has been studied in vivo in CHO cells and in vitro in reticulocyte lysates by using the pseudosubstrate O(6)-benzylguanine (BG) and mutant forms of AGT. The wild-type AGT was stable but was ubiquitinated and degraded rapidly by the proteasome after treatment with BG or with an oligodeoxyribonucleotide, which contained O(6)-methylguanine. Mutants C145F (and other mutants with bulky substituents at position 145), which have alterations that cause a steric alteration at the active site and also prevent hydrogen bonding involving Cys-145 resembled the alkylated AGT and were ubiquitinated and degraded rapidly irrespective of treatment with BG. Mutant M134F, which causes a steric alteration without interfering directly with the hydrogen-bonding network involving Cys-145, partially destabilized AGT and its degradation was increased further by reaction with BG. Mutant C145S, which maintains the hydrogen-binding network and causes no distortion, was not rapidly degraded. The results indicate that the conformational change resulting in the opening of the asparagine hinge region in the structure, which is brought about by formation of an S-alkyl adduct, leads to an increased recognition by a ubiquitin ligase targeting the protein for degradation. This is a novel type of post-translational modification causing ubiquitination.
Carcinogenesis 2002 May
PMID:Degradation of the alkylated form of the DNA repair protein, O(6)-alkylguanine-DNA alkyltransferase. 1201 56

Helicobacter pylori infection is associated with increased gastric epithelial cell turnover and is a risk factor for noncardia gastric cancer. H. pylori reduces the expression of p27 protein, a cyclin-dependent kinase inhibitor of the G(1) to S-phase cell cycle transition and gastric tumor suppressor gene. Although cell cycle dysregulation associated with decreased p27 may contribute to gastric carcinogenesis, how H. pylori reduces p27 in gastric epithelial cells remains unknown. In the present study, we investigated the mechanisms of the p27 decrease, using AGS and MKN28 gastric epithelial cells cocultured with H. pylori strains under conditions of defined cell cycle distribution. The expression of p27 protein was reduced by H. pylori in a dose- and time-dependent manner. Northern blot and pulse-chase analyses revealed that this reduction was not regulated at a transcriptional level but by accelerated p27 degradation via a proteasome-dependent pathway. Despite up-regulation of the proteasome-dependent degradation of p27 protein, neither threonine 187-phosphorylated p27 nor skp2 (the ubiquitin ligase for p27) were increased. Furthermore, H. pylori impaired p27 ubiquitination and did not increase global proteasomal function. These results indicate that H. pylori increases the degradation of p27 through a proteasomal pathway distinct from the physiological pathway that degrades p27 during cell cycle progression. Putative virulence genes of H. pylori (cagA, cagE, or vacA) played no role in reducing p27 expression. Increased degradation of p27 by H. pylori through a proteasome-dependent, ubiquitin-independent pathway may contribute to the increased risk of gastric cancer associated with chronic H. pylori infection.
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PMID:Helicobacter pylori increases proteasome-mediated degradation of p27(kip1) in gastric epithelial cells. 1290 57

Tripartite motif protein 32, Trim32, mRNA and protein expression was elevated in independently transformed and tumorigenic keratinocytes of a mouse epidermal carcinogenesis model, in ultraviolet B (UVB)-induced squamous cell carcinomas (SCC), and in approximately 20-25% of chemically induced mouse papillomas and human head and neck SCCs. This suggests that elevated Trim32 expression occurs frequently in experimental epidermal carcinogenesis and is relevant to human cancer. Transduced Trim32 increased colony number in an epidermal in vitro transformation assay and epidermal thickening in vivo when skin-grafted to athymic nu/nu mice. These effects were not associated with proliferation and were not sufficient for tumorigenesis, even with 12-O-tetradecanoylphorbol-13-acetate treatment or defects in the tumor suppressor p53. However, transduced Trim32 inhibited the synergistic effect of tumor necrosis factor alpha (TNFalpha) on UVB-induced apoptosis of keratinocytes in vitro and the apoptotic response of keratinocyte grafts exposed to UVB-light in vivo. Consistent with its RING domain, Trim32 exhibited characteristics of E3-ubiquitin ligases, including being ubiquitylated itself and interacting with ubiquitylated proteins, with increases in these properties following treatment of cultured keratinocytes with TNFalpha/UVB. Interestingly, missense point mutation of human TRIM32 has been reported in Limb-Girdle Muscular Dystrophy Type 2H, an autosomal recessive disease. We propose a model in which Trim32 activities as an E3-ubiquitin ligase favor initiated cell survival in carcinogenesis by blocking UVB-induced TNFalpha apoptotic signaling.
Carcinogenesis 2004 Feb
PMID:RING protein Trim32 associated with skin carcinogenesis has anti-apoptotic and E3-ubiquitin ligase properties. 1457 65

The mitotic checkpoint is a failsafe mechanism for the cell to ensure accurate chromosome segregation during mitosis. Mutations in genes encoding essential checkpoint proteins lead to chromosome instability and promote carcinogenesis. The BUB and MAD genes are essential components of the mitotic checkpoint pathway. BUB and MAD inhibit the ubiquitin ligase activity of the Anaphase Promoting Complex/Cyclosome (APC/C) during mitosis to ensure cells with unaligned chromosomes do not prematurely enter anaphase. Two models explain how the APC/C is inhibited by the checkpoint. The Sequestration Model postulates that Mad2 and BubR1 bind and sequester Cdc20, an APC/C activator, away from APC/C so substrates whose destruction drives mitotic exit are no longer ubiquitinated. In this model, the unattached kinetochore is postulated to catalytically convert Mad2 to a form that binds Cdc20. In the Direct Inhibition Model, the Mitotic Checkpoint Complex (MCC) consisting of BubR1, Bub3, Mad2 and Cdc20 binds and inhibits the APC/C independently of the kinetochore. However, the "wait anaphase" signal generated by unattached kinetochores sensitizes the APC/C to prolonged inhibition by the MCC. A single unattached kinetochore is proposed to amplify the "wait anaphase" signal through a kinase cascade involving checkpoint kinases such as hBubR1, hBub1 and Mps1.
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PMID:The mitotic checkpoint: a signaling pathway that allows a single unattached kinetochore to inhibit mitotic exit. 1459 37

The regulation of protein stability by the ubiquitin-proteasome pathway is a critical issue central to the comprehension of the molecular basis of carcinogenesis. However, ubiquitin modification of target substrates signals many cellular processes other than proteolysis that are also important for the development of cancer. It is noteworthy that many proteins studied by clinical breast cancer researchers are involved in these ubiquitin pathways. This review summarizes recent works on such proteins including cyclins, CDK inhibitors, and the SCF in cell cycle control; the breast and ovarian cancer suppressor BRCA1-BARD1; ErbB2/HER2/Neu and its ubiquitin ligase c-Cbl or CHIP; and the estrogen receptor and its downstream target Efp. Understanding these pathways may provide some hints toward developing diagnostic tools and treatments for breast cancer patients.
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PMID:Ubiquitin and breast cancer. 1502 95

Retinoblastoma gene product (pRB) plays critical roles in regulation of the cell cycle and tumor suppression. It is known that downregulation of pRB can stimulate carcinogenesis via abrogation of the pRB pathway, although the mechanism has not been elucidated. In this study, we found that Mdm2, a ubiquitin ligase for p53, promoted ubiquitin-dependent degradation of pRB. pRB was efficiently ubiquitinated by wild-type Mdm2 in vivo as well as in vitro, but other RB family proteins were not. Mutant Mdm2 with a substitution in the RING finger domain showed dominant-negative stabilization of pRB. Both knockout and knockdown of Mdm2 caused accumulation of pRB. Moreover, Mdm2 inhibited pRB-mediated flat formation of Saos-2 cells. Downregulation of pRB expression was correlated with a high level of expression of Mdm2 in human lung cancers. These results suggest that Mdm2 regulates function of pRB via ubiquitin-dependent degradation of pRB.
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PMID:Enhanced Mdm2 activity inhibits pRB function via ubiquitin-dependent degradation. 1557 44

The function of the human papillomavirus (HPV) E6 protein that is most clearly linked to carcinogenesis is the targeted degradation of p53, which is dependent on the E6AP ubiquitin ligase. Additional functions have been attributed to E6, including the stimulation of telomerase activity and the targeted degradation of other cellular proteins, but in most cases it is unclear whether these activities are also E6AP dependent. While E6 clearly influences the transcriptional program of HPV-positive cell lines through the inactivation of p53, it has been shown that at least a subset of its p53-independent functions are also reflected in the transcriptional program. For this study, we have determined the extent to which E6AP is involved in mediating the set of E6 functions that impact on the global transcriptional program of HPV-positive cell lines. The transcriptional profiles of approximately 31,000 genes were characterized for three cell lines (HeLa, Caski, and SiHa cells) after small interfering RNA (siRNA)-mediated silencing of E6 or E6AP. We found that E6 and E6AP siRNAs elicited nearly identical alterations in the transcriptional profile of each cell line. Some of the expression alterations were apparent secondary effects of p53 stabilization, while the basis of most other changes was not reconcilable with previously proposed E6 functions. While expression changes of the TERT gene (telomerase catalytic subunit) were not revealed by the array, telomerase repeat amplification protocol assays showed that both E6 and E6AP knockouts resulted in a suppression of telomerase activity. Together, these results suggest that E6AP mediates a broad spectrum of E6 functions, including virtually all functions that impact on the transcriptional program of HPV-positive cell lines.
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PMID:The global transcriptional effects of the human papillomavirus E6 protein in cervical carcinoma cell lines are mediated by the E6AP ubiquitin ligase. 1573 Dec 67

Helicobacter pylori infection is associated with increased gastric epithelial cell turnover and non-cardia gastric cancer. Cell cycle progression is dependent on the proteasomal degradation of p27, a cyclin-dependent kinase inhibitor and gastric tumor suppressor, following ubiquitination mediated by Skp2. c-Myc is a transcriptional repressor of p27 and also a target of Skp2. In vitro, H. pylori decreases p27 protein post-translationally. We aimed to determine how p27 is regulated by H. pylori in vivo. The effect of eradicating H. pylori on gastric epithelial p27, Skp2, and c-Myc proteins and mRNA was investigated in 22 patients with chronic gastritis, by immunohistochemistry and laser capture microdissection. The percentage of gastric antral epithelial cells expressing p27 protein was significantly higher after eradication of H. pylori (mean+/-s.e.m. 37+/-2.4% pre-eradication vs 55+/-2.8% post-eradication; P<0.001), while Skp2 and c-Myc protein-expressing cells were lower (Skp2: 35+/-3.8 vs 23+/-2.6%, P=0.009; c-Myc: 47+/-3.6 vs 30+/-3.8%, P<0.001). mRNA expressions of p27, Skp2, and c-Myc (normalized for 18SrRNA) were not changed by H. pylori eradication. H. pylori increases c-Myc and decreases gastric epithelial p27 protein expression in association with increased expression of Skp2, the regulator of p27's ubiquitin ligase complex. H. pylori may influence cell cycle progression and carcinogenesis through post-translational effects on specific gene expression.
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PMID:Altered expression of Skp2, c-Myc and p27 proteins but not mRNA after H. pylori eradication in chronic gastritis. 1611 28


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