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

The von Hippel-Lindau (VHL) tumor suppressor protein is the substrate binding subunit of the CBC(VHL) E3 ubiquitin ligase complex. Mutations in the VHL gene cause a variety of tumors with complex genotype/phenotype correlations. Type 2A and type 2B VHL disease are characterized by a low or high risk of renal cell carcinoma, respectively. To investigate the molecular basis underlying the difference between disease types 2A and 2B, we performed a detailed biochemical analysis of the two most frequent type 2A mutations, Y98 H and Y112 H, in comparison to type 2B mutations in the same residues, Y98N and Y112N. While none of these mutations affected the assembly of CBC(VHL) complexes, the type 2A mutant proteins exhibited higher stabilities at physiological temperature. Moreover, the type 2A mutant proteins possessed higher binding affinities for the key cellular substrate, hypoxia-inducible transcription factor 1 (HIF-1alpha). Consistent with these results, type 2A but not type 2B mutant VHL proteins retained significant ubiquitin ligase activity towards HIF-1alpha in vitro. We propose that this residual ubiquitin ligase activity is sufficient to suppress renal cell carcinogenesis in vivo.
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PMID:Renal cell carcinoma risk in type 2 von Hippel-Lindau disease correlates with defects in pVHL stability and HIF-1alpha interactions. 1626 Nov 65

Fragile histidine triad (FHIT), a candidate of tumor suppressor protein, expression was examined on paraffin-embedded specimens in proliferative, secretory, hyperplastic, and neoplastic human endometrium by immunohistochemistry. The results of FHIT immunoreactivity in endometrial carcinomas were compared with prognostic indicators as well as with p53 overexpression. Forty-four cases of endometrial carcinoma, 30 normal functional (15 proliferative, 15 secretory), and 24 hyperplastic endometrium (12 without atypia, 12 with atypia) specimens were studied using polyclonal FHIT antibody. The streptavidin-biotin-peroxidase detection system was used, and the intensity and the distribution of immunoreactivity were evaluated semiquantitatively. There were no significant differences in FHIT expression in the proliferative, secretory, hyperplastic, either with or without atypia, or carcinomatous endometria. No significant difference in FHIT expression of endometrial carcinomas was detected when prognostic parameters or p53 overexpression were considered. Loss or reduced FHIT expression was not found to predict disease-free or cumulative survivals. This study showed that loss or reduction in FHIT protein expression is present in normal functional and hyperplastic endometria as well as in neoplastic endometrium. FHIT protein seems not to be involved directly in endometrial carcinogenesis, but rather, it regulates cell proliferation both in physiologic and in pathologic conditions of endometrium.
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PMID:FHIT expression in neoplastic, hyperplastic, and normal endometrium. 1634 85

The tumor suppressor protein phosphatase and tensin homologue deleted on chromosome ten (PTEN) plays an important role in intestinal cell proliferation and differentiation and tumor suppression by antagonizing phosphatidylinositol 3-kinase. Despite its importance, the molecular mechanisms regulating PTEN expression are largely undefined. Here, we show that treatment of the colon cancer cell line HT29 with the differentiating agent sodium butyrate (NaBT) increased PTEN protein and mRNA expression and induced c-Jun NH2-terminal kinase (JNK) activation. Inhibition of JNK by chemical or genetic methods attenuated NaBT-induced PTEN expression. In addition, our findings showed a cross-talk between nuclear factor kappaB (NF-kappaB) and JNK with respect to PTEN regulation. Overexpression of the NF-kappaB superrepressor increased PTEN expression and JNK activity, whereas overexpression of the p65 NF-kappaB subunit reduced both basal and NaBT-mediated JNK activation and PTEN expression. Moreover, we showed that overexpression of PTEN or treatment with NaBT increased expression of the cyclin-dependent kinase inhibitor p27(kip1) in HT29 cells; this induction was attenuated by inhibition of PTEN or JNK expression or overexpression of p65. Finally, we show a role for PTEN in NaBT-mediated cell death and differentiation. Our findings suggest that the JNK/PTEN and NF-kappaB/PTEN pathways play a critical role in normal intestinal homeostasis and colon carcinogenesis.
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PMID:Regulation of PTEN expression in intestinal epithelial cells by c-Jun NH2-terminal kinase activation and nuclear factor-kappaB inhibition. 1769 82

Objective and reproducible assessment of cancer biomarkers may be performed using rare event detection systems. Because many biomarkers are not true 'rare events', in this study a semi-rare event detection system was developed. The system is capable of assigning a discriminant score to detected positive cells, expressing the extent and intensity of the immunocytochemical staining. A gallery image is constructed showing the diagnostically most interesting cells as well as quantitative data expressing the biomarker staining pattern. To increase scanning speed, an adaptive scanning strategy is studied in which scanning is aborted when a sufficient number of positive cells has been identified. System performance was evaluated using liquid based cervical smears, stained with an antibody directed against p16(INK4a) tumor suppressor protein. Overexpression of p16(INK4a) in cervix is related to high-risk HPV infection, which is associated with carcinogenesis. Reproducibility of the system was tested on specimens containing limited positivity. Quantitative analysis was evaluated using 10 cases within normal limits and 10 high grade lesions. The system was highly reproducible in detecting positive cells and in calculating discriminant scores (average CV 0.7%). Quantitative features were significantly increased in high grade lesions (p<0.001). Adaptive scanning decreased scanning time with only minor impact on scanning results. The system is capable of automated, objective and reproducible assessment of biomarker expression and may be useful for a variety of applications.
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PMID:Objective assessment of cancer biomarkers using semi-rare event detection. 1803 25

Hepatitis B virus X protein (HBx) is essential for hepatitis B virus infection and exerts a pleiotropic effect on various cellular machineries. HBx has been also demonstrated as an indirect transcriptional transactivator of various different viral and cellular promoters. In addition, HBx is involved in the development of various liver diseases including hepatocellular carcinoma. However the mechanism of HBx in hepatocellular carcinogenesis remains largely unknown. In this study, to identify possible new cellular proteins interacting with HBx, we carried out yeast two-hybrid assay. We obtained several possible cellular partners including VBP1, a binding factor for VHL tumor suppressor protein. The direct physical interaction between HBx and VBP1 in vitro and in vivo was confirmed by immunoprecipitation assay. In addition, we found that VBP1 facilitates HBx-induced NFkappaB activation and cell proliferation. These results implicate the important role of HBx in the development of hepatocellular carcinoma through its interaction with VBP1.
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PMID:Hepatitis B virus X protein enhances NFkappaB activity through cooperating with VBP1. 1831 53

The CHFR protein comprises fork head associated- (FHA) and RING-finger (RF) domain and is frequently downregulated in human colon and gastric cancers up to 50%. The loss of CHFR mRNA expression is a consequence of promoter methylation, suggesting a tumor suppressor role for this gene in gastrointestinal carcinogenesis. In terms of the biological functions of CHFR, it has been shown to activate cell cycle checkpoint when cells are treated with microtubule depolymerizing agents. Furthermore, CHFR was reported to have E3 ligase activity and promote ubiquitination and degradation of oncogenic proteins such as Aurora A and polo-like kinase 1. However, molecular pathways involved in the tumor suppressive function of CHFR are not yet clear since the two established roles of this protein are likely to inhibit cell growth. In this study, we have identified that the FHA domain of CHFR protein is critical for growth suppressive properties, whereas the RF and cysteine rich domains (Cys) are not required for this function. In contrast, the RF and Cys domains are essential for E3 ligase activity of CHFR. By the use of a cell cycle checkpoint assay, we also confirmed that the FHA domain of CHFR plays an important role in initiating a cell cycle arrest at G2/M, indicating a functional link exists between the anti-proliferative effects and checkpoint function of this tumor suppressor protein via this domain. Collectively, our data show that the checkpoint function of the FHA domain of CHFR is a core component of anti-proliferative properties against the gastrointestinal carcinogenesis.
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PMID:The anti-proliferative effects of the CHFR depend on the forkhead associated domain, but not E3 ligase activity mediated by ring finger domain. 1833 50

The objective of the current study was to investigate the effects of Rap1GAP on invasion and progression of head and neck squamous cell carcinoma (SCC) and the role of matrix metalloproteinase (MMP) 9 and MMP2 in this process. Rap1GAP functions by switching off Rap1, the Ras-like protein that has been associated with carcinogenesis. Previous findings suggest that Rap1GAP acts as a tumor suppressor protein in SCC by delaying the G(1)-S transition of the cell cycle. However, cells transfected with Rap1GAP exhibit a more invasive phenotype than corresponding vector-transfected control cells. MMP2 and MMP9 are enzymes that mediate SCC invasion via degradation of the extracellular matrix. Using SCC cells transfected with empty vector or Rap1GAP, cell invasion and MMP secretion were determined by Matrigel assays and gelatin zymography, respectively. Rap1GAP up-regulated transcription and secretion of MMP2 and MMP9, as assayed by quantitative reverse transcription-PCR and zymography. Furthermore, chemical and RNA interference blockade of MMP2/MMP9 inhibited invasion by Rap1GAP-transfected cells. Immunohistochemical staining of a human oropharyngeal SCC tissue microarray showed that Rap1GAP and MMP9 expression and staining intensity are correlated (P < 0.0001) and that, in early N-stage lesions of SCC, high MMP9 is prognostic of poor disease-specific survival (P < 0.05). Furthermore, Rap1GAP staining is correlated with MMP2 (P < 0.03). MMP2 in combination with N stage has a prognostic effect on time to indication of surgery at primary site. MMP2 intensity is also positively correlated with T stage (P < 0.015). In conclusion, Rap1GAP inhibits tumor growth but induces MMP2- and MMP9-mediated SCC invasion and tumor progression, suggesting a role for this protein as a biomarker for early N-stage, aggressive SCCs.
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PMID:Rap1GAP promotes invasion via induction of matrix metalloproteinase 9 secretion, which is associated with poor survival in low N-stage squamous cell carcinoma. 1848 82

Viral-induced carcinogenesis has been attributed to the ability of viral oncoproteins to target and interact with the host cellular proteins. It is generally accepted that Human papilloma virus (HPV) E6 and E7 function as the dominant oncoproteins of 'high-risk' HPVs by altering the function of critical cellular proteins. Initially it was shown that HPV E6 enhances the degradation of p53, while HPV E7 inactivates the function of the retinoblastoma tumor suppressor protein Rb. However, recent studies during the last decade have identified a number of additional host cellular targets of both HPV E6 and E7 that may also play an important role in malignant cellular transformation. In this review we present the interactions of HPV E6 and E7 with the host cellular target proteins. We also present the role of DNA integration in the malignant transformation of the epithelial cell.
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PMID:Human papilloma virus (HPV) and host cellular interactions. 1849 68

Among the most promising pathways for molecular targets in sporadic epithelial ovarian cancer (SEOC) are those involving the BRCA1 protein. Because somatic mutations in BRCA1 are rare in SEOC, it was originally postulated that BRCA1 plays a limited role in the pathogenesis of this disease. However, inactivation of BRCA1 through various mechanisms is a relatively frequent event in ovarian cancer. This is important because BRCA1 is involved in the cellular response to DNA damage and repair and has an essential role in the maintenance of genomic stability. The BRCA1 tumor suppressor protein is known to interact with genes and proteins known collectively as the BRCA1 pathway, and defects in this pathway are believed to be a driving force for cancer progression. As a result, there is compelling evidence to suggest that the dysfunction of BRCA1 may be a central mechanism in all ovarian carcinogenesis, and this has clinical and molecular significance beyond the management of patients with hereditary ovarian cancer. The aim of this review is to evaluate the evidence for BRCA1 dysfunction in SEOC and to link this dysfunction to a defective DNA repair pathway and ultimately the promotion of genomic instability and tumorigenesis. Furthermore, we advocate the continued need to study BRCA1 and its pathway by prospectively correlating clinicopathologic data with molecular aberrations. This will determine whether BRCA1 has relevance as a predictive and prognostic marker in SEOC and whether aberrations in the BRCA1 pathway warrant further study as potential therapeutic targets.
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PMID:Sporadic epithelial ovarian cancer: clinical relevance of BRCA1 inhibition in the DNA damage and repair pathway. 1859 60

We performed comparative proteomic analysis of colorectal cancer to investigate potential target proteins correlated with carcinogenesis and prognosis. Among them, transgelin, a 22 kDa protein also called SM22, was identified as a novel tumor suppressor protein, but little is known about this protein in tumors so far. A remarkable reduced expression of transgelin was found in colorectal cancer samples compared with normal colorectal mucosa. The effect of 5-aza-2'-deoxycytidine as a demethylation agent would obviously restore the original expression level of transgelin, implicating DNA hypermethylation of transgelin is important in the regulation of transgelin transcription in colorectal cancer. As a control, the investigation at cell line level confirms that transgelin protein comes from epithelium but not mesenchymal cells. Further, immunohistochemical staining for transgelin was performed on paraffin sections of 62 and 126 cases of normal colorectal mucosa and colorectal cancer specimens, respectively. As compared to normal colorectal tissue, we observed a significantly lower transgelin expression in colorectal cancer samples (P<0.001). Survival analysis demonstrated that patients without transgelin expression had shorter overall survival, whereas patients with transgelin expression had better survival (P=0.006). Multivariate analysis showed that negative transgelin expression was an independent prognostic indicator for patient's survival. Our results suggest that transgelin as a suppressor may serve as important biomarker of malignancy. Loss of transgelin involves gene promoter hypermethylation and is closely associated with poor overall survival in colorectal cancer patients.
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PMID:Transgelin as a suppressor is associated with poor prognosis in colorectal carcinoma patients. 1932 40


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