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:1.11.1.6 (catalase)
55,569 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Overexpression and point mutation of the p53 protein/gene was investigated in a series of chondrosarcoma by an immunohistochemical approach, and direct sequencing of the genomic DNA, respectively. In 2 of the 16 cases studied, both of which were high grade chondrosarcomas (grade III), immunodetectable p53 was identified. Histologically, one was ordinary type and the other a clear cell variant. However, no positivity was observed in the other cases including nine of low grade, ordinary type, three of low grade, clear cell type, and two of extraskeletal myxoid chondrosarcoma. Direct sequencing, following polymerase chain reaction amplification of exons 5-9 of the p53 gene in 14 cases, in which fresh materials were available, successfully demonstrated base substitution mutations in only two cases with detectable p53 overexpression on immunohistochemistry. Their details were GTC (valine) to TTC (phenylalanine) at codon 157 in exon 5, and CGT (arginine) to CAT (histidine) at codon 273 in exon 8. No mutation was detected in the other 12 cases which were negative for p53 immunostaining. These findings strongly suggest that p53 mutation plays a crucial role in the biologically aggressive subtype, and possibly in the process of tumor progression in human chondrosarcoma.
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PMID:Possible association of p53 overexpression and mutation with high-grade chondrosarcoma. 811 3

DNA from tumor tissue and peripheral blood lymphocytes of primary breast cancer patients was screened for the presence of p53 mutations. In DNA from one tumor we found that the histidine codon 193 (CAT) was somatically converted to arginine (CGT). This amino acid residue is highly conserved in many species, thus suggesting that such mutation plays an important role in the loss of wt-p53 function.
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PMID:A novel p53 mutant in human breast cancer revealed by multiple SSCP analysis. 818 56

Cells with divergent mutant alleles of the p53 gene have different biological and biochemical properties in vitro. Increasing evidence indicates that p53 is a transcriptional activator, and recently, high affinity DNA binding sites for p53 have been identified. The purpose of this study was to determine in vivo, the effect that various mutant p53 proteins have on their ability to mediate transactivation and to bind specifically to DNA. Either a p53 responsive or control reporter gene was transfected into 18 human carcinoma cell lines, having various p53 mutations, either with or without a wild-type p53 expression vector. The CAT activity and DNA gel retardation were studied to measure transactivation and DNA binding by these endogenous p53s. As expected, the endogenously produced wild-type p53 binds to DNA binding sequences and can transactivate a reporter construct containing a p53 high affinity DNA binding site. Four of five cell lines with homozygous p53 mutations at codon 273 (273His), contained p53 which had the ability to bind to p53 DNA binding sequences and transactivate. In contrast, all the homozygous, non-codon 273 mutant p53s (156Pro, 175His, 223Leu, 248Gln, 248Trp, 280Lys) present in the other cell lines had no transactivating ability. These findings suggest that the biology of cancers with mutations at codon 273 may be different than those with p53 mutations at other sites. The p53 from WRO, a thyroid carcinoma cell line with p53 mutation at codon 223 (223Leu), was able to bind p53 DNA recognition sequences, but was unable to transactivate. Interestingly, in a vulvar carcinoma cell line (A431) with a p53 mutation at codon 273 (273His), the p53 was unable to transactivate and gave an aberrant band on gel retardation. Both CEM and SK-UT-1, which have compound heterozygous mutations at codons 175/248 (175His/248His), produced p53 which can complex with DNA, as well as transactivate. In contrast, the p53 in cell lines with either homozygous 175His or 248His p53 mutations, were unable either to transactivate or bind to the p53 response element. A cell line (NPA) heterozygous for 266Glu p53 mutation, was able to efficiently transactivate a reporter containing a p53 DNA binding site, therefore showing no evidence of a dominant negative effect of the endogenous p53 mutant allele. In summary, this in vivo study further supports the idea that different p53 mutant alleles have various properties which may affect their function.
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PMID:Transactivational and DNA binding abilities of endogenous p53 in p53 mutant cell lines. 820 36

An analysis of cell lines representing different stages of the B-cell differentiation pathway indicated that about 50% of the cell lines examined expressed exclusively wild type p53 protein. These lines therefore offer a convenient system to study the involvement of p53 in cell differentiation. When 70Z/3, a pre-B cell line which expresses wild type p53, was treated with the differentiation inducer lipopolysaccharide (LPS), it was seen that increased levels of p53 mRNA preceded specific changes in kappa (kappa) immunoglobulin expression. This increased expression of kappa specific mRNA, which was evaluated by specific PCR analysis, was blocked following transfection with mutant p53 coding plasmids. Treatment of 13A60, another cell line which endogenously expresses wild type p53, with LPS caused a secretion of IgA antibodies, also accompanied by increased p53 mRNA expression. The conclusion was that induction of B-cell differentiation involves the transcription of the p53 gene. This was further substantiated by experiments showing that differentiation of stable clones derived from the 70Z/3 cell line, harboring a p53-promoter-CAT plasmid, induced increased CAT activity. Furthermore, wild type p53 transactivated the promoter control sequences of the kappa light chain gene. Taken together, these results suggest that p53 is involved in B-cell differentiation, a pathway which involves DNA rearrangements that may be accompanied by generation of faulty DNA. The fact that wild type p53 was shown to function as a transcriptional factor, coupled with the notion that it is associated with DNA repair systems, may designate p53 as a control protein in the B-cell differentiation pathway.
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PMID:Wild type p53 functions as a control protein in the differentiation pathway of the B-cell lineage. 824 32

A rare germ-line polymorphism in codon 47 of the p53 gene replaces the wild-type proline (CCG) with a serine (TCG). Restriction analysis of 101 human samples revealed the frequency of the rare allele to be 0% (n = 69) in Caucasians and 4.7% (3/64, n = 32) among African-Americans. To investigate the consequence of this amino acid substitution, a cDNA construct (p53 mut47ser) containing the mutation was introduced into a lung adenocarcinoma cell line (Calu-6) that does not express p53. A growth suppression similar to that obtained after introduction of a wild-type p53 cDNA construct was observed, in contrast to the result obtained by introduction of p53 mut143ala. Furthermore, expression of neither p53 mut47ser nor wild-type p53 was tolerated by growing cells. In transient expression assays, both mut47ser and wild-type p53 activated the expression of a reporter gene linked to a p53 binding sequence (PG13-CAT) and inhibited the expression of the luciferase gene under the control of the Rous sarcoma virus promoter (RSVluc). In the same assay, mut143ala did not activate the expression of PG13-CAT and produced only a slight inhibitory effect on RSVluc. These findings indicate that the p53 variant with a serine at codon 47 should be considered as a rare germ-line polymorphism that does not alter the growth-suppression activity of p53.
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PMID:Functional studies of a germ-line polymorphism at codon 47 within the p53 gene. 835 80

Recent evidence suggests that the tumor-suppressor protein p53 functions as a transcriptional regulator to control cell proliferation. An interaction with p53 is required for SV40 T antigen to transform primary cells; however, the effect of T antigen binding on p53 function is not known. In order to determine if an interaction with T antigen results in loss of p53-mediated transcriptional activity, we have used vectors expressing either a p53-GAL4 fusion protein or a wild-type p53 protein in transient co-transfection assays with T-antigen expression vectors. We have demonstrated that coexpression of T antigen significantly reduces both p53-GAL4-mediated transcription from a GAL4-dependent CAT reporter and p53-mediated transcription from a consensus p53 binding site in vivo. Moreover, T antigen was able to reduce binding of p53-GAL4 to its GAL4 binding sequence in gel shift experiments in vitro. These observed activities of T antigen were all dependent upon a functional p53-binding domain. In addition, coexpression of human papillomavirus type 18 E6 protein, able to bind to p53, was able to significantly reduce p53-mediated transcription. These results suggest that an interaction of certain viral oncoproteins with p53 results in loss of transcriptional activity of p53, a function that is important for maintaining normal cell growth.
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PMID:SV40 T antigen abrogates p53-mediated transcriptional activity. 837 89

Human papillomavirus (HPV) infection is clearly associated with cervical carcinomas, yet it is also true that there are cervical carcinomas in which HPV DNA is absent. We examined eight established cell lines derived from cervical carcinomas for the presence of mutations of the p53 antioncogene in relation to the presence of HPV DNA sequences. Of these eight cell lines, seven were positive for HPV DNA and the remaining one was negative for HPV DNA. Single-strand conformation polymorphism analyses revealed a point mutation of the p53 gene in the cell line in which HPV DNA was absent. Sequencing analysis revealed a single-base mutation at codon 273 from CGT to CAT(Arg-->His) and immunocytochemical studies provided evidence that the p53 protein was overexpressed in this cell line. Our observations suggest that the loss of normal p53 gene function may be linked to the oncogenesis of cervical carcinoma.
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PMID:Correlation between HPV positivity and state of the p53 gene in cervical carcinoma cell lines. 838 Jul 85

p53 is known to bind specifically to the 44-bp human DNA sequence in an immunoprecipitation assay. We show here that the transcription of the reporter CAT gene linked with the herpesvirus thymidine kinase (tk) promoter containing the 44-base sequence is enhanced by mouse wild-type but not mutant-type p53 in F9 and p53-null Saos-2 cells. The p53-mediated transactivation was dramatically abrogated by introduction of SV40 large T antigen (SVLT) in Saos-2 cells in which p53 was clearly associated with SVLT. Furthermore, the p53-SVLT complex did not bind to the 44-base sequence at all. Thus, SVLT sequesters the transactivation function of the wild-type p53 by inhibiting the binding of p53 to the 44-base sequence. This is good evidence to show 'loss of functions' in the product of a tumor-suppressor oncogene by a dominant oncogene product at a molecular level.
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PMID:Abrogation of p53-mediated transactivation by SV40 large T antigen. 838 54

A variety of neoplasms of the human nervous system were analyzed for the presence of mutations in the p53 tumor suppressor gene. DNA was extracted from frozen or formalin-fixed, paraffin-embedded material. Single-strand conformation polymorphism (SSCP) analysis for exons 5-8 was followed by direct DNA sequencing. Mutations leading to an amino acid change were found in three of 11 (27%) low-grade (World Health Organization (WHO) Grade II) astrocytomas. They were located in codon 183 (TCA-->TGA) of exon 5, codon 237 (ATG-->ATA) of exon 7, and codon 273 (CGT-->CAT) of exon 8. In one of these cases, the sequence indicated loss of the wild-type allele. Of 12 juvenile pilocytic astrocytomas (WHO Grade I), none contained a p53 mutation, suggesting a different molecular basis for this childhood neoplasm. Except for a mutation in one of seven (14%) meningeal hemangiopericytomas (codon 238; TGT-->TTT, Cys-->Phe), no mutations were observed in exons 5-8 of the p53 gene in any of the following tumors of the nervous system and its coverings: 13 schwannomas, 12 central neurocytomas, 22 meningiomas, 10 choroid plexus papillomas and carcinomas, and 30 neuroblastomas of the sympathetic nervous system. These and published data support the view that p53 mutations are frequently involved both in low-grade and progressive (anaplastic) astrocytomas, including glioblastomas multiforme. Oligodendrogliomas, medulloblastomas, meningiomas, and hemangiopericytomas rarely (< 15%) show p53 mutations in exons 5-8, whereas none of the remaining nervous system neoplasms revealed evidence of an involvement of the p53 gene in their development.
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PMID:Mutations of the p53 tumor suppressor gene in neoplasms of the human nervous system. 839 97

Alterations or elimination of the p53 protein is frequently occurring during human carcinogenesis. Overexpression of wild-type p53 has a profound growth-inhibitory effect on many cell lines, including strong and apparently non-sequence specific repression of a number of promoters. Consistent with the hypothesis that it acts as transcriptional regulator, wild-type p53 protein binds DNA and activates transcription of several promoters. We have studied DNA binding and transactivation (TA) properties of human wild-type and mutant p53 proteins representing four major mutational hotspots. DNA-gel retardation was used to detect specific p53-DNA complexes in nuclear extracts, with radiolabelled oligonucleotides representing high affinity p53-binding sites (HBS) as a probe. p53-specific complexes were identified by competition with unlabelled 'self' oligos and by double band-shifts in the presence of anti-p53 antibodies. To show transactivation by p53, TK promoter-driven CAT reporter gene was placed 3' of the p53-binding site. CAT activity was assayed after co-transfection of reporters with either wild-type (WT) or mutant p53 expression constructs into human cells that do not express p53 (SKOV3). We found that wild-type p53 has strong transactivating effect on the reporter. All mutants, with the exception of His273, were inactive in TA-assay. p53 is a target of several oncogenes found in DNA tumor viruses. We examined the effect of either SV40 T-ag or 55 kDa EIB protein of Ad5 on DNA binding and transactivation by p53 in transformed COS-1 and 293 cell lines, respectively. COS-1 extracts produced strong p53-dependent band-shift of the HBS oligos, that was doubleshifted by anti-p53 but not anti-T-ag antibodies, indicating that T-ag is not part of the complex. COS-1 cells had a high level of WT p53-dependent expression of transfected CAT reporter, indicating the presence of transactivation-competent p53, acting through the HBS element. In human Ad-transformed 293 cells, endogenous p53 was also transactivation competent and capable of DNA binding. In summary, we found efficient transactivation of HBS motif by WT and His273-p53. Studies of COS-1 and 293 cells suggest that a proportion of p53 in transformed cells display wild-type DNA binding and TA properties and that expression of transcriptionally inactive mutant p53 proteins in these cells does not interfere with WT-dependent transactivation.
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PMID:Analysis of p53 transactivation through high-affinity binding sites. 841 2


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