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)

Activation of telomerase compensating for the loss of telomeres has been implicated in human cell immortalization and carcinogenesis. Telomeric repeat amplification protocol (TRAP) assay can be used to detect telomerase activity in a variety of malignant tumours, including those of the female reproductive tract which have been found to have high levels of telomerase activity. However, it is unclear whether all the cells or only a subset of cells within a tumour have telomerase activity. To determine the regulation mechanism of telomerase activity in hydatidiform moles, we studied telomerase activity at the single cell level (using an in situ TRAP assay), and expression of TLP1 (telomerase protein 1), TERC (telomerase RNA component) and TERT (telomerase reverse transcriptase component). Expression of TERC and TLP1 was observed in all normal chorionic villi, as well as in trophoblastic diseases, and various cell lines irrespective of telomerase activity. TERT expression was observed in trophoblastic diseases and normal chorionic villi with telomerase activity but not in normal chorionic villi without telomerase activity, except in some cases in the present series, indicating that TERT expression is closely associated with telomerase activity. Upregulation of TERT expression may thus play an important role in telomerase reactivation.
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PMID:Expression of telomerase subunits and localization of telomerase activation in hydatidiform mole. 1032 53

An accumulation of multiple genetic and epigenetic alterations of oncogenes, tumor suppressor genes, DNA repair genes, cell cycle regulators, cell adhesion molecules, and the growth factor/receptor system is involved in the course of multistep conversion of normal epithelial cells to clinical gastric cancer. Some of them differ depending on the histological type, well-differentiated (intestinal) and poorly differentiated (diffuse) types, suggesting the presence of two distinct genetic pathways. Genetic instability, chromosomal instability (telomere reduction), and immortality (activation of telomerase and expression of telomerase reverse transcriptase: TERT) participate in the initial step of stomach carcinogenesis. Because TERT protein expression precedes the telomerase activities in precancerous lesions, TERT expression may be a prerequisite for telomerase activation. The cyclin E gene is amplified in 15%-20% of gastric cancer. Reduced expression of a cyclin-dependent kinase (CDK) inhibitor, p27Kip1, is frequently found in gastric cancer associated with high grade malignancy. E2F-1, an important downstream target of cyclins/CDKs, is overexpressed in about 40% of gastric carcinomas, whereas gene amplification of E2F-1 rarely occurs. Loss of heterozygosity (LOH) of p73, the p53-related new tumor suppressor gene, preferentially occurs in well-differentiated adenocarcinomas of foveolar type expressing pS2, a gastric-specific trefoil factor, indicating the importance of p73 LOH in the genesis.
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PMID:Genetic and epigenetic alterations in multistep carcinogenesis of the stomach. 1077 29

Inhibition of telomerase is proposed to limit the growth of cancer cells by triggering telomere shortening and cell death. Telomere maintenance by telomerase is sufficient, in some cell types, to allow immortal growth. Telomerase has been shown to cooperate with oncogenes in transforming cultured primary human cells into neoplastic cells, suggesting that telomerase activation contributes to malignant transformation. Moreover, telomerase inhibition in human tumour cell lines using dominant-negative versions of TERT leads to telomere shortening and cell death. These findings have led to the proposition that telomerase inhibition may result in cessation of tumour growth. The absence of telomerase from most normal cells supports the potential efficacy of anti-telomerase drugs for tumour therapy, as its inhibition is unlikely to have toxic effects. Mice deficient for Terc RNA (encoding telomerase) lack telomerase activity, and constitute a model for evaluating the role of telomerase and telomeres in tumourigenesis. Late-generation Terc-/- mice show defects in proliferative tissues and a moderate increase in the incidence of spontaneous tumours in highly proliferative cell types (lymphomas, teratocarcinomas). The appearance of these tumours is thought to be a consequence of chromosomal instability in these mice. These observations have challenged the expected effectiveness of anti-telomerase-based cancer therapies. Different cell types may nonetheless vary in their sensitivity to the chromosomal instability produced by telomere loss or to the activation of telomere-rescue mechanisms. Here we show that late-generation Terc-/- mice, which have short telomeres and are telomerase-deficient, are resistant to tumour development in multi-stage skin carcinogenesis. Our results predict that an anti-telomerase-based tumour therapy may be effective in epithelial tumours.
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PMID:Telomerase-deficient mice with short telomeres are resistant to skin tumorigenesis. 1097 62

Topical application of 7,12-dimethylbenz(alpha)-anthracene induces tumors in the hamster cheek pouch. Telomerase activity is increased in the cancer tissues if compared to normal adjacent tissues in both human and hamster oral cancer. In order to achieve a probe and to investigate the putative role of telomerase in oral carcinogenesis using the hamster cheek pouch model, we have cloned the cDNA encoding the hamster telomerase catalytic subunit (hamTERT). The hamster TERT cDNA encoded 1128 amino acids and shared 64% amino acid identity with human TERT and 80% with murine TERT. As noted with human TERT which express several alternatively spliced mRNAs, we have also detected one alternatively spliced hamTERT mRNA in hamster cancer cells. Transient transfection of hamTERT cDNA in a retroviral expression vector reconstituted telomerase activity in the telomerase negative human lung fibroblast IMR90 cells.
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PMID:Cloning and expression of hamster telomerase catalytic subunit cDNA. 1140 53

The hamster and human TERT promoters share common critical protein binding sites, such as the GC-box or E-box, which is known to be a binding site for Sp1/Sp3 transcriptional factors and c-Myc, respectively. Our previous data demonstrated that Sp1/Sp3 synergistically transactivate the hamster TERT (hamTERT) promoter. In this study, we determined the role of c-Myc in the regulation of hamTERT, and analyzed the relative significance of GC-boxes and the E-box for transcriptional activation of hamster TERT. Wild-type, mutated E-box or mutated GC-box hamTERT core promoter reporter was introduced into 293T cells in combination with murine or human Myc expression vectors. The promoter activity was determined using the luciferase assay, and the transfection efficiency was normalized with CAT activity. The electrophoretic mobility shift assay (EMSA) was done to prove the nuclear protein binding activity of the GC-box (region II) or E-box. Overexpression of murine or human Myc transactivated hamTERT core promoter activity. Inversion mutation in the E-box or substitution mutation in the GC-boxes abrogated endogenous or Myc induced hamTERT transactivation. Region II is the single most important Sp1/3 binding site in transcriptional activation, and multiple combined mutations in the GC-boxes abolished the hamTERT promoter activity. These results indicate that c-Myc and Sp1/3 are the major regulatory determinants of the hamTERT transcriptional activation. The mechanism of TERT gene activation during immortalization and carcinogenesis may be conserved among species.
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PMID:c-Myc and Sp1/3 are required for transactivation of hamster telomerase catalytic subunit gene promoter. 1156 51

We tested 30 laryngeal squamous cell carcinomas (LSCCs) and 30 matched control laryngeal samples from the same patients for the presence of human telomerase catalytic subunit (hTERT) mRNA by using the Roche LightCycler Telo TAGGG hTERT Quantification kit. The hTERT index was calculated to express the relative quantity levels of hTERT mRNA. hTERT mRNA was detectable in 10 out of 30 (33%) laryngeal tissues covered by normal and/or reactively hyperplastic laryngeal epithelium and 23 out of 30 LSCCs (77%). The mean hTERT indices were 0.15 for control non-cancerous laryngeal samples, 0.57 for grade I, 2.35 for grade II and 3.72 for grade III LSCCs. LSCCs without detectable hTERT mRNA (23%) tended to have lower grades of disease. No correlation was found between the levels of hTERT mRNA and tumour size or locoregional lymph node status. We believe that hTERT mRNA in normal and/or reactively hyperplastic laryngeal epithelium originates from the stem cells and corresponds to the self-renewal capacity of the squamous epithelium. However, the greater quantity of h TERT mRNA in LSCCs is the result of telomerase reactivation in the process of laryngeal carcinogenesis.
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PMID:Quantitative measurement of telomerase catalytic subunit (hTERT) mRNA in laryngeal squamous cell carcinomas. 1191 Dec 85

Many cancer and immortal cells exhibit telomerase activity that stabilizes telomere lengths, possibly contributing to cell immortality and carcinogenesis. The aim of this study was to elucidate the clinicopathological relationship between telomerase activity and telomerase reverse transcriptase subunit (hTERT) status in non small cell lung cancer. hTERT status in non small cell lung cancer using telomeric repeat amplification protocol (TRAP) and RT-PCR assay, respectively. Telomerase activity and hTERT were detected in 85.7 and 80.3% of cancerous tissues, respectively. Telomerase activity does not correlate with clinicopathological variables. However, there was an association between p53-correlated expression and hTERT negative status. Lung cancer patients without telomerase activity survived for a significantly longer period than those with telomerase activity. In addition, hTERT was not associated with the prognosis. TERT expression did not correlate well with any clinical parameter. Reactivated telomerase activity may be a poor prognostic factor in NSCLCs.
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PMID:Loss of telomerase activity may be a potential favorable prognostic marker in lung carcinomas. 1287 79

Telomerase activity is present in most malignant tumors and provides a mechanism for unlimited replication of neoplastic cells. This study was undertaken to investigate the expression of the gene encoding human telomerase reverse transcriptase (hTERT), the telomerase catalytic subunit gene in lung carcinoma, by in situ hybridization (ISH). hTERT is associated with telomerase activity, and overexpressed in most lung carcinomas. We assayed hTERT gene expression by ISH to study telomerase activity in lung carcinomas of 27 patients, and compared these results with those of telomerase activity by telomeric repeat amplification protocol (TRAP) assay. TERT gene expression by ISH was detected mainly in the nuclei of lung carcinoma cells. Some specimens showed a significant expression in only infiltrating lymphocytes. hTERT gene expression by ISH was found in 16 of 27 (59%) cases. On the other hand, telomerase activity by TRAP assay was detected in 21 of 27 (78%) cases. In 7 cases, TRAP assay detected telomerase activity, but ISH did not detect hTERT expression. TRAP assay might detect telomerase activity in not only carcinoma cells, but also in infiltrating lymphocytes. Our findings therefore suggest that ISH-based analysis of hTERT gene expression is superior to TRAP assay as a means of determining telomerase status during carcinogenesis.
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PMID:Demonstration of human telomerase reverse transcriptase by in situ hybridization in lung carcinoma. 1554 42

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

The transcriptional regulation of the human telomerase catalytic subunit (hTERT) plays a critical role in telomerase activity. Approximately 200 bp of the proximal core promoter is responsible for basic hTERT expression; however, the function of the distal regulatory elements remains unclear. The transcription factor activator protein 1 (AP-1) is involved in cellular proliferation, differentiation, carcinogenesis, and apoptosis and is expressed broadly in both cancer and normal cells. There are several putative AP-1 sites in the hTERT promoter, but their functions are unknown. The present study examined the regulatory role of AP-1 in hTERT gene transcription. Overexpression of AP-1 leads to transcriptional suppression of hTERT in cancer cells. The combination of c-Fos and c-Jun or c-Fos and JunD strongly suppresses hTERT promoter activity in transient-expression analyses. The hTERT promoter region between -2000 and -378 is responsible for this function. Gel shift and supershift analyses, as well as ChIP, show binding of JunD and c-Jun on two putative AP-1 sites within this region. Mutations in the AP-1 binding sites rescued suppressions caused by AP-1, suggesting this is a direct regulation of the hTERT promoter. In contrast, there was no effect on mTERT expression or mTERT promoter activity by AP-1 overexpression in mouse fibroblasts. The species-specific function of AP-1 in TERT expression may in part help explain the difference in telomerase activity between normal human and mouse cells.
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PMID:Function of AP-1 in transcription of the telomerase reverse transcriptase gene (TERT) in human and mouse cells. 1613 95


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