Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.27.1 (RNase)
16,360 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

p73, the gene for a protein related to the tumor suppressor p53, encodes several variants which bear distinct carboxy-terminal structures as a result of alternative splicing. We and others showed that these splicing variants have different transcriptional effects on promoters with a p53-binding consensus sequence (p53BCS). Here we show that when transiently overexpressed, p73alpha but not p73beta activated several minimal promoters without the p53BCS, while p73gamma and p73epsilon activated them to a much lesser extent than p73alpha, and p53 suppressed the promoters without p53BCS as reported previously. Moreover, the results of RNase protection and RNA transfection assays suggested that this activation occurred at the transcriptional level. Deletion analysis of p73alpha revealed that the transactivation domain of p73 was not involved in this activity and the C-terminal region of p73alpha which is a specific structure of this variant was essential, suggesting that this phenomenon occurs independent of the transactivation activity of p73alpha and that the C-terminal extension of p73alpha may affect the basal level of transcription.
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PMID:Overproduced p73alpha activates a minimal promoter through a mechanism independent of its transcriptional activity. 1173 4

Gamma-glutamylcysteine synthetase (gamma-GCS) is a heterodimer consisting of heavy (gamma-GCSh) and light (gamma-GCSl) subunits. gamma-GCS catalyzes the rate-limiting de novo biosynthesis of glutathione (GSH), an abundant physiological antioxidant that plays important roles for regulating oxidative stress. Expression of gamma-GCSh and gamma-GCSl are sensitive to oxidative stress. To investigate whether expression of gamma-GCS is correlated with tumor progression, we used immunohistochemical approaches to examine 16 human colorectal adenomas and resected 57 carcinomas from untreated patients. In adjacent normal colorectal epithelium, levels of gamma-GCSh expression were low. Strong cytoplasmic staining for gamma-GCSh was detected in 3 (18.8%) adenoma and 48 (84.2%) carcinomas. The frequency of gamma-GCSh expression in carcinoma was significantly higher than in adenoma (p<0.0001). We used RNase protation assay and Western blot to determine levels of gamma-GCSh mRNA and protein from 10 pairs of matched carcinomas with adjacent normal controls. Elevated expression of both gamma-GCSh mRNA and protein were found in 6 cases, suggesting that transcriptional and/or posttranscriptional regulation play an important role in the upregulation of gamma-GCS during colorectal carcinogenesis. We also examined the expression of another redox-regulated gene, multidrug resistance protein 1 (MRP1). Strong staining for MRP1 was detected in 1 (6.3%) adenoma and 40 (70.2%) carcinomas. The frequency of MRP1 expression in carcinoma was significantly higher than in adenoma ( p<0.0001). Nuclear p53 expression was detected in 30 (52.6%) of carcinomas. There is a significant correlation between gamma-GCSh and MRP1 expression (p=0.013) but not between gamma-GCSh and p53. Since gamma-GCS is a sensor of oxidative stress, these results are consistent with the notion that oxidative stress is associated with colorectal tumor progression.
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PMID:Expression of heavy subunit of gamma-glutamylcysteine synthetase (gamma-GCSh) in human colorectal carcinoma. 1177 39

The protein product of the ING1 gene physically interacts with p53 and appears necessary for the role of p53 in growth inhibition/apoptosis. Alternative splicing of the ING1 gene produces three transcripts: p24/ING1-ALT1, p47/ING1-ALT2 and p33/ING1. A competitive RT-PCR, which determines the relative levels of these transcripts, was employed to study peripheral blood lymphocytes from 49 patients with haematological malignancies and five normal controls. Both groups expressed predominantly the p33/ING1 transcript, with low levels of p24/ING1 and p47/ING1. We screened the complete p33/ING1 transcript for sequence variations, by non-isotopic RNase cleavage assay (NIRCA); none were found. This study suggests that neither perturbation of alternative splicing, nor mutation of p33/ING1 plays a significant role in the development of haematological malignancies.
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PMID:Relative levels of alternative transcripts of the ING1 gene and lack of mutations of p33/ING1 in haematological malignancies. 1200 79

Angiogenesis is a prominent feature of glioblastomas but the mechanisms involved in the control of this process are poorly understood. We have investigated the potential role of a recently described transcription factor, hypoxia-inducible factor 1 (HIF-1), which initiates the transcription of a number of hypoxia-inducible genes, including those encoding vascular endothelial growth factor and its receptors. HIF-1 protein expression was assessed by immunocytochemistry, using a monoclonal antibody to the alpha subunit (HIF-1alpha). HIF-1 mRNA expression was assessed by reverse transcriptase-polymerase chain reaction (RT-PCR) and the ribonuclease protection assay (RPA). Strong nuclear expression of HIF-1alpha protein was seen in the majority of glioblastomas and anaplastic astrocytomas, particularly surrounding areas of necrosis in glioblastomas. In the majority of these tumours upregulation of HIF-1alpha mRNA was also demonstrated, with a significant increase in glioblastomas compared to lower grade tumours. No correlation was found between the presence of HIF-1alpha protein and immunohistochemical expression of p53 protein. These findings are in keeping with an important role of HIF-1alpha in the vascularization of glioblastomas and suggest that upregulation is at least partly at a transcriptional level.
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PMID:Expression of hypoxia-inducible factor 1alpha in tumours of patients with glioblastoma. 1206 Mar 45

Previously, we reported that human papillomavirus (HPV) type 16 E6 binds to C/H1, C/H3, and the C-terminal domains of coactivators p300 and CBP, causing the modulation of the transcription of certain genes controlled by NF-kappaB (p65 or relA) and p53. To establish the biological significance of these observations, we have focused on the transcriptional regulation of interleukin-8 (IL-8), a potent chemoattractant for T lymphocytes and neutrophils, which is also essential for the initiation of the local immune response. The IL-8 promoter is regulated by NF-kappaB/p65 in response to tumor necrosis factor alpha and requires the cooperation of the coactivators CBP/p300 and steroid receptor coactivator 1 (SRC-1) and the p300/CBP-associated factor (P/CAF) for optimal activation. Here we report that, in the presence of HPV-16 E6, the promoter activity of IL-8 was repressed. Moreover, from the mutational analysis of the IL-8 promoter, we found that E6 down-regulates the IL-8 promoter activity through the NF-kappaB/p65 binding site. This inhibition appears to result from the ability of HPV-16 E6 to compete with NF-kappaB/p65 and SRC-1 for binding to the N terminus and C terminus of CBP, respectively. Reporter data also showed that E7 represses IL-8 promoter activity, though to a lesser extent than E6 but, like E6, the repression by E7 is through the NF-kappaB/p65 binding site. E7 was shown for the first time to bind to P/CAF, and the binding was necessary for the down regulation of the IL-8 promoter. E6 and E7 together inhibited transcription of the IL-8 promoter to a greater extent than either alone. Finally, by RNase protection assay, we showed that the synthesis of endogenous IL-8 mRNA was repressed in keratinocytes stably expressing E6 and E7. Taken together, the results provide evidence that E6 and E7 can cooperatively disrupt IL-8 transcription through disruption of transcriptional active complexes, and this may have important consequences for immune responses in infected hosts.
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PMID:Down regulation of the interleukin-8 promoter by human papillomavirus type 16 E6 and E7 through effects on CREB binding protein/p300 and P/CAF. 1216 91

Recurrent respiratory papillomatosis (RRP), caused by the human papillomavirus, is characterized by unregulated growth of wartlike neoplasms on laryngeal mucosa. Apoptosis is important in normal cellular homeostasis, and dysregulation of this process is thought to govern the behavior of certain neoplasms. This study evaluates the expression of several pro-apoptotic and anti-apoptotic factors in papillomas of patients with RRP, with a specific interest in survivin, a cell cycle-regulated anti-apoptotic factor. Three anti-apoptotic and 6 pro-apoptotic messenger RNA (mRNA) species were quantified by ribonuclease protection assay in 11 RRP papilloma specimens and 5 normal laryngeal specimens. Anti-apoptotic and pro-apoptotic mRNA ratios were quantified by normalizing to the ribosomal protein L32 and compared between specimens. Protein expression of survivin in tissue samples was also evaluated. The mean (+/- SD) expression of survivin was almost fivefold greater in the RRP papillomas than in normal tissue (14.2% +/- 2.5% versus 3.0% +/- 0.8% of L32, p = .003). The RRP specimens also had greater expression of XIAP, Fas, and p53 than did the normal tissue. Survivin protein was differentially expressed in the papilloma specimens, and was greatest in a papilloma that underwent malignant transformation. Survivin was absent in all normal laryngeal tissue tested. Apoptotic factors in general appear to be upregulated in papillomatous tissue as compared to normal laryngeal tissue and may suggest a higher proliferation rate and cell turnover. Survivin is abundant in papillomas and absent in normal laryngeal tissue. Dysregulation of apoptosis as determined by abnormal expression of anti-apoptotic factors like survivin and XIAP probably favors papilloma growth and survival. Such factors may represent potential targets in the treatment of this disease.
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PMID:Survivin expression in juvenile-onset recurrent respiratory papillomatosis. 1245 Jan 66

In order to study the response of T cells to IL-7, we aimed to generate an IL-7-dependent thymocyte line. CD4(-)CD8(-) thymocytes from a p53(-)/(-) mouse were continuously propagated in interleukin-7 (IL-7), and after 2 months there developed an immortal line termed "D1." The D1 line has retained a stable dependency on IL-7. Withdrawal of IL-7 from D1 cells induced arrest in G1 phase of the cell cycle, followed by apoptosis. In addition to IL-7, several other cytokines that employ gamma(c) as part of their receptor were also capable of stimulating D1 cell survival and proliferation. Gene induction by IL-7 was analyzed in D1 cells using RNase protection and array analysis and revealed a number of transcripts potentially involved in cell cycle, apoptosis and signaling.
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PMID:Characterization of an interleukin-7-dependent thymic cell line derived from a p53(-/-) mouse. 1260 43

p21 (Waf1/Cip1) is a downstream target of p53. We evaluated the association between p21 polymorphism (codon 31), p53 polymorphism (codon 72) and their corresponding in vivo mRNA expression. In this study, p21 and p53 genetic polymorphisms (using standard PCR-RFLP techniques) and p21 and p53 gene expressions (using a radiolabelled ribonuclease protection assay (RPA) technique) were evaluated in the peripheral leukocytes of 84 individuals (63 with lung cancer). Log-transformed values of mRNA expression by RPA, which approximated a normal distribution, were analyzed. p53 genotypes did not correlate with p53 mRNA log-expression (P>0.05 for all comparisons), but the Pro allele variants of p53 were associated with a significant decrease in mRNA log-expression of its downstream target, p21. The variant Arg allele of p21 was also associated with a significant decrease in p21 mRNA log-expression. When individuals with at least one variant allele of both p53 and p21 (double-variants) were compared with all other genotype groups, these double-variants had significantly lower log-expression of p21 (P<0.005 by both t-tests (crude) and linear regression analyses (adjusted)). This is translated into an approximate 48% reduction in the geometric mean of the mRNA expression of the double-variants, when compared with all other groups. Results were consistent in both patients with lung cancer (n=63) and in normal controls (n=21). In conclusion, the presence of a p53 Pro allele and/or p21 Arg allele is associated with lower downstream target gene expression of p21.
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PMID:P53 (codon 72) and P21 (codon 31) polymorphisms alter in vivo mRNA expression of p21. 1278 24

The present study was undertaken to evaluate p53 gene mutation as a prognostic factor in patients with colorectal cancer. Nonisotopic RNase cleavage assay (NIRCA), recently used for detecting gene mutations, was employed to detect p53 gene mutations in this study. In 15 samples of colorectal tumors, NIRCA was confirmed to be simple, accurate, and thus useful for clinical use, compared with polymerase chain reaction single-strand conformational polymorphism (PCR-SSCP). In another group of 79 cases of colorectal cancer analyzed for p53 gene mutation by using NIRCA, mutations were detected in 58 of 79 (73.4%) cases. Multivariate Cox proportional-hazards analysis showed that p53 gene mutation was a significant prognostic factor in patients with colorectal cancer. Our results showed that NIRCA is a simple and sensitive method, and thus useful for genetic screening of colorectal cancer. Furthermore, our results showed that p53 gene mutation is an independent predictor of poor prognosis in colorectal cancers.
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PMID:Detection of p53 gene mutations by nonisotopic RNase cleavage assay as a predictor of poor prognosis in colorectal cancers. 1462 45

Adenoviral p53 gene transfer (Ad-p53) induces apoptosis in glioma cells expressing mutant p53, but fails in cells with wild-type p53. Endogenously, gliomas express varied levels of Fas/CD95, yet constitutively high levels of Fas/CD95 ligand. Because the mechanism behind the differential apoptotic response to Ad-p53 infection remains elusive, we examined how the Fas/CD95 pathway is involved in U87MG (wt-p53), D54 (wt-p53), U251MG (mutant-p53), and U373MG (mutant-p53) glioma cell lines. Ad-p53 infection did not alter the levels of Fas/CD95 ligand in either wild-type or mutant p53-expressing cell lines. In contrast, Ad-p53 infection led to an approximately 3-fold increase in Fas/CD95 mRNA expression in mutant p53-bearing cell lines but not in their wild-type (wt) counterparts, as assessed in an RNase protection assay. Fas/CD95 mRNA induction appeared to be regulated at the transcriptional level because Ad-p53 infection resulted in up to a 4-fold increase in Fas/CD95 promoter reporter activity. Subsequently, flow cytometric analysis revealed a 2- to 4-fold increase in surface Fas/CD95 expression following Ad-p53 infection in mutant-p53-containing cell lines. Use of the protein transport inhibitor Brefeldin A significantly inhibited Ad-p53-induced surface Fas/CD95 expression, but only partially inhibited apoptosis in mutant-p53 cell lines. These results suggest that p53 regulates Fas/CD95 expression at the transcriptional level and through protein trafficking in mutant-p53 cell lines. Fluorogenic activity assays demonstrated that induction of caspase-8 activity following Ad-p53 infection correlated with increases in Fas/CD95 expression. Incubating cells with a caspase-8-specific inhibitor Ac-IETD-CHO prior to Ad-p53 infection inhibited caspase-8 activity and apoptosis. Together, our results suggest that regulation of the Fas/CD95 pathway is partly responsible for Ad-p53-induced apoptosis in glioma cells, which depends on the p53 status of the involved cells. Additionally, the inability of Ad-p53 to activate the Fas/CD95 pathway in wt-p53 glioma cells coincides with their apoptotic-resistant phenotype. Further elucidation of the nature of this resistance could ultimately augment the efficacy of Ad-p53 gene therapy.
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PMID:Differential activation of the Fas/CD95 pathway by Ad-p53 in human gliomas. 1471 18


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