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: UNIPROT:P04637 (p53)
77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To further investigate the role of p53 gene inactivation in gastric tumorigenesis, the mutational status of the p53 gene in primary human gastric cancer samples was examined. Reverse transcriptase polymerase chain reaction and subsequent direct sequencing of the p53 gene from gastric cancer samples revealed frequent point mutations of the p53 gene: some of these coincided with those previously identified in gastric cancer cell lines. In addition, both allelic deletion analysis using pYNZ 22 and polymerase chain reaction-restriction fragment length polymorphism analysis demonstrated an allelic deletion of the p53 gene in cancer tissue which contained a point mutation of the p53 gene in the remaining allele. Transfection of the wild-type or mutant p53 genes into gastric cancer cells showed that the wild-type but none of the mutated p53 genes suppressed the colony formation of gastric cancer cells. Furthermore, the incorporation of thymidine into DNA was reduced in cancer cells expressing the wild-type p53 gene. The glutathione S-transferase-wild type p53 fusion protein bound to simian virus 40 large T antigen in COS-1 cell lysate. None of the p53 fusion proteins containing mutations at codons 143, 175, 248, or 273 bound to simian virus 40 large T antigen. By contrast, two different mutant p53 fusion proteins containing mutations specifically observed in gastric cancer bound to simian virus 40 large T antigen. These results indicate that inactivation of the p53 gene through mutations and the allelic deletion may play an important role in gastric tumorigenesis. These mutations may cause a conformational change in the p53 protein resulting in the loss of the suppression by p53 of the growth of gastric cells, partly through disruption of the association of p53 protein with a cellular component.
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PMID:p53 gene mutations in human gastric cancer: wild-type p53 but not mutant p53 suppresses growth of human gastric cancer cells. 132 85

Cell cycle checkpoints appear to contribute to an increase in cell survival and a decrease in abnormal heritable genetic changes following exposure to DNA damaging agents. Though several radiation-sensitive yeast mutants have been identified, little is known about the genes that control these responses in mammalian cells. Recent studies from our laboratory have demonstrated a close correlation between expression of wild-type p53 genes in human hematopoietic cells and their ability to arrest in G1 phase after certain types of DNA damage. In the present study, this correlation was first generalized to nonhematopoietic mammalian cells as well. A cause and effect relationship between expression of wild-type p53 and the G1 arrest that occurs after gamma irradiation was then established by demonstrating (i) acquisition of the G1 arrest after gamma irradiation following transfection of wild-type p53 genes into cells lacking endogenous p53 genes and (ii) loss of the G1 arrest after irradiation following transfection of mutant p53 genes into cells with wild-type endogenous p53 genes. A defined role for p53 (the most commonly mutated gene in human cancers) in a physiologic pathway has, to our knowledge, not been reported previously. Furthermore, these experiments illustrate one way in which a mutant p53 gene product can function in a "dominant negative" manner. Participation of p53 in this pathway suggests a mechanism for the contribution of abnormalities in p53 to tumorigenesis and genetic instability and provides a useful model for studies of the molecular mechanisms of p53 involvement in controlling the cell cycle.
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PMID:Wild-type p53 is a cell cycle checkpoint determinant following irradiation. 132 40

Aberrations of the p53 gene in 115 surgical specimens of non-small cell carcinomas of the lung were examined by single-strand conformation polymorphism analysis of polymerase chain reaction products. Structural abnormalities of the p53 gene were observed in 60 tumors (52%), i.e., 8 of 14 large cell carcinomas, 24 of 58 adenocarcinomas, 25 of 37 squamous cell carcinomas, and 3 of 6 adenosquamous carcinomas. Direct sequencing of abnormal DNA fragments revealed 45 single-base substitutions, 9 deletions or insertion of a short nucleotide sequence, and 3 two-base substitutions in 57 tumors. In the other 3 tumors, loss of one of the p53 alleles was observed, with no mutation in the other allele. Allelic loss of the p53 gene was observed in 14 of 43 informative cases (33%), and in 11 of the 14 cases the remaining allele was mutated. The aberrations of the p53 gene were not limited to a particular histological type or clinical stage. Their high frequency suggests that they were involved in the genesis of non-small cell carcinomas of the lung. The mutation frequency (46%) of the p53 gene in tumors carrying mutated ras genes was essentially the same as the overall frequency in lung cancers, suggesting that accumulation of mutations in these two genes in a tumor is a random phenomenon.
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PMID:Aberrations of the p53 tumor suppressor gene in human non-small cell carcinomas of the lung. 132 94

Little is known regarding the molecular genetic events in head and neck carcinoma. Epidemiological evidence suggests that both alcohol and tobacco use are related to the development of these neoplasms, and viral infections have also been postulated to play a role in some tumors. Loss of p53 tumor suppressor gene function has been found in many malignancies and can occur through either gene mutation or by interaction with the E6 protein of oncogenic human papilloma viruses (HPV). Because the mucosal surfaces of the head and neck are exposed to mutagens and HPVs, we studied DNA derived from 30 stage I-IV squamous cell carcinomas of the head and neck (9 primary tumors and 21 early passage cell lines) for p53 gene mutations as well as for the presence of oncogenic HPV DNA. Exons 2 through 11 of the p53 gene were examined using single strand conformation polymorphism analysis followed by direct genomic sequencing of all variants. HPV detection was done using polymerase chain reaction amplification with HPV E6 region type specific primers as well as L1 region degenerate ("consensus") primers; HPV type was determined by restriction fragment length polymorphism analysis of the amplified fragment as well as by Southern blotting of genomic DNA. Sixteen of 30 tumors (53%) had p53 mutations and oncogenic HPV DNA was detected in 3 of 30 (10%) tumors, none of which had p53 mutations. The p53 mutational spectrum observed was characterized by equal frequencies of transversions (6 of 16), transitions (5 of 16), and deletions (5 of 16). This distribution of mutations differs from the spectrum of p53 mutation reported in esophageal (P = 0.05) and lung (P = 0.02) cancers, two other tobacco associated neoplasms. A previously undescribed clustering of 3 mutations at codon 205 was also observed. A trend toward a shorter time to tumor recurrence after treatment was noted for those patients with tumors exhibiting p53 gene mutations, and no relationship between p53 mutations and tumor stage or node status was noted. Alteration in p53 gene function appears common in head and neck cancer, and the mutational spectrum observed may reflect the role of different mutagens or mutagenic processes than those responsible for the p53 mutations in lung and esophageal neoplasms.
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PMID:Occurrence of p53 gene deletions and human papilloma virus infection in human head and neck cancer. 132 97

A method using selective ultraviolet radiation fractionation followed by polymerase chain reaction (PCR) can analyze specific cell subsets present on a microscope section. Direct ultraviolet radiation of fixed and stained tissue sections prevents subsequent amplification by PCR. An "umbrella" or dot placed physically over small numbers of pure cell populations selected by microscopic examination protects these cells from the ultraviolet inactivation. The DNA in these protected cells can be specifically amplified while no signal is derived from the unprotected surrounding cells. Specific amplification was demonstrated by detecting human papillomavirus sequences only if infected cells were protected. Similarly, loss of heterozygosity at the p53 locus was documented by selective dotting of normal or tumor cells. The method allows the specific and sensitive molecular genetic analysis of small numbers of cells histologically identified and selected under the microscope.
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PMID:Specific genetic analysis of microscopic tissue after selective ultraviolet radiation fractionation and the polymerase chain reaction. 132 39

In the past year, new data have been published on the molecular biology of human papillomavirus infections and their relationship to cervical neoplasia. As molecular techniques have become more sophisticated and as the molecular knowledge of human papilloma-virus infections has been pursued in greater depth, it is increasingly apparent that this human tumor DNA virus is similar to a number of other oncogenic DNA viruses that have been described and well studied. These viruses appear to act through a common pathway of producing oncogenic proteins that interfere with key signalling elements that normally control the process of cell division. With a better mechanistic knowledge, it should be possible to design new therapeutic approaches to treating human papillomavirus-associated disease that are directed toward specific cellular events such as turning off the production of E6 and E7 proteins or restoring the activity of pRB or p53. Increased attention has also been turned to immunologic aspects of HPV infections, and a number of groups are eagerly pursuing the possibility of using simple office-based procedures to detect specific proteins encoded for by the human papillomavirus open reading frames in an attempt to determine who has been infected, is actively infected, and has proteins being produced that are indicative of neoplasia. From the clinical point of view, the use of outpatient excisional techniques such as the loop electrosurgical excision procedure is rapidly supplanting ablative techniques because of their superior ability to identify early invasive carcinomas and adenocarcinomas in situ that have not been detected by colposcopy.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Human papillomavirus. 132 50

A previous report using cervical carcinoma cell lines suggests that the inactivation of two tumor suppressor gene products, p53 and pRB, either by complex formation with the E6 and E7 proteins of oncogenic human papillomaviruses (HPVs) or by mutation, may be an important step in cervical carcinogenesis (M. Scheffner et al., Proc. Natl. Acad. Sci. USA, 88: 5523-5527, 1991). The present study was designed to clarify the association between p53 inactivation and infection with oncogenic HPVs in primary carcinomas of human uterine cervix. We examined 36 primary cervical carcinomas for the presence of HPV DNAs by Southern blot analysis with probes specific for HPV-16, -18, -31, -33, -52, -56, and -58. HPV DNA sequences were detected in 19 of 36 tumors: 10 cases with HPV-16; 3 cases with -18; 3 cases with -58; 2 cases with -56; and one case with -52. The presence of HPV-16 and -18 in cervical carcinomas was further reexamined using polymerase chain reaction. HPV DNA sequences were detected in an additional 10 cases: 9 cases with -16 and one case with -18. The inactivation of the p53 gene by allelic loss or by point mutation was also examined. No allelic loss at the polymorphic site in codon 72 of the p53 gene was detected in any of 10 informative cases. Missense point mutations in the highly conserved regions of the p53 gene were demonstrable as single-stranded conformational polymorphisms of polymerase chain reaction-amplified DNA fragments and subsequently identified by direct DNA sequencing. Point mutations were detected in only two cases: one with an ATG----CTG transversion in codon 133 of exon 5, resulting in a Met----Leu substitution, and another with a CGG----TGG transition in codon 248 of exon 7, resulting in an Arg----Trp substitution. Both tumors with point mutations in p53 genes were among 10 tumors which contained a small copy number of HPV-16 DNA sequences (1 copy of HPV/10(1) to 10(5) cells) detectable by polymerase chain reaction amplification but not by Southern blot analysis of genomic DNAs derived from the tumors. None of 19 tumors with a large copy number of HPV DNA sequences detectable by Southern blot analysis (more than 1 copy of HPV/2 to 10 cells) nor any of 7 tumors with undetectable HPV DNA sequences contained p53 gene mutations in the regions examined.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Alterations of the p53 gene in human primary cervical carcinoma with and without human papillomavirus infection. 132 6

Genomic rearrangements occurring in C3H/10T1/2 cells transformed by X-rays were examined with a DNA fingerprint assay. Four multilocus and multiallele probes were employed (M, X, H10, and H16) that detect different families of minisatellite sequences dispersed throughout the genome. Genomic rearrangements were detectable only with probe M. This specificity may be explained by a genomic instability owing to a specific sequence or structure of DNA recognized by probe M. Genomic rearrangements were detected in 5 of 12 type III foci transformed by 600 cGy of X-rays and in all clones isolated from a previously transformed clone exposed to a second dose of 600 cGy and recloned. The latter data suggest that the stage of transformation and the occurrence of genomic rearrangement induced by X-rays may be related. An intensity shift or a complete deletion of band 2 was common to these X-ray-induced clones, as well as to clones transformed by UV-C (1 of 5) or 3-methylcholanthrene (4 of 6). This band did not hybridize to probes for the retinoblastoma gene RB or for p53. We hypothesize that the loss of band 2 may reflect a significant genetic change in the transformation of 10T1/2 cells, perhaps representing the inactivation of a tumor suppressor gene other than RB or p53. Additional rearrangements occurred in X-ray-transformed clones; these rearrangements were not observed with the other carcinogens. Aside from the changes in band 2, however, no specific pattern of genomic rearrangement was associated with X-ray transformation, and the presence or absence of rearrangements did not correlate with tumorigenicity in syngeneic nonimmunosuppressed C3H mice.
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PMID:Genomic rearrangements in mouse C3H/10T1/2 cells transformed by X-rays, UV-C, and 3-methylcholanthrene, detected by a DNA fingerprint assay. 132 16

The 21-bp repeat region of simian virus 40 (SV40) activates viral transcription and DNA replication and contains binding sites for many cellular proteins, including Sp1, LSF, ETF, Ap2, Ap4, GT-1B, H16, and p53, and for the SV40 large tumor antigen. We have attempted to reduce the complexity of this region while maintaining its growth-promoting capacity. Deletion of the 21-bp repeat region from the SV40 genome delays the expression of viral early proteins and DNA replication and reduces virus production in CV-1 cells. Replacement of the 21-bp repeat region with two copies of DNA sequence motifs bound with high affinities by Sp1 promotes SV40 growth in CV-1 cells to nearly wild-type levels, but substitution by motifs bound less avidly by Sp1 or bound by other activator proteins does not restore growth. This indicates that Sp1 or a protein with similar sequence specificity is primarily responsible for the function of the 21-bp repeat region. We speculate about how Sp1 activates both SV40 transcription and DNA replication.
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PMID:Two synthetic Sp1-binding sites functionally substitute for the 21-base-pair repeat region to activate simian virus 40 growth in CV-1 cells. 132 72

Recent studies of the p53 tumor suppressor locus (designated TP53) in primary hepatocellular carcinoma (PHC) have identified a high frequency of codon 249 mutations. Due to the geographic location from which the samples were obtained and the substitution observed, the mutation was suggested to be attributable to aflatoxin B1 (AFB1) exposure. To determine the generality of this phenomenon, we have examined PHC tissues from 107 geographically and ethnically diverse sources. The frequency of p53 gene mutations was evaluated by using PCR/restriction-digest methods, GC-clamp (G+C-rich sequence) denaturing gradient gel electrophoresis, and DNA sequencing. The mutation rate observed in tumors from high-AFB1-exposure regions (25%) was more than double the rate observed in low-exposure regions (12%) but lower than the 50% frequency previously reported. Codon 249 mutations occurred at a much lower frequency than previously reported (2 of 107 samples examined). These results suggest that changes in DNA encoding p53 may not represent primary oncogenic effects but instead represent genetic changes related to tumor progression. High AFB1 levels may facilitate the generation of these progressional changes, but not by inducing a specific p53 gene mutation at codon 249 as previously reported.
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PMID:Low frequency of p53 mutations observed in a diverse collection of primary hepatocellular carcinomas. 132 3


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