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)

Limited information is currently available on chromosomal abnormalities in esophageal adenocarcinoma and associated premalignant lesions. In this study, numeric changes affecting chromosomes 4, 6, 7, 8, 9, 10, 11, 12, 17, 18, X, and Y were analyzed by using fluorescence in situ hybridization (FISH) with chromosome-specific centromere DNA probes in 12 esophageal adenocarcinomas. In addition, TP53 overexpression, measured by immunohistochemistry, and amplification of HER-2/neu and C-MYC, detected by FISH, were analyzed within the same tumors. The most common numeric abnormalities detected were gains of chromosomes 12 (8 cases), 6 (7 cases), 7 (7 cases), and 11 (6 cases). The total number of abnormal chromosomes varied from 0 to 10, with an average of 4.6 per case. Overexpression of TP53 was present in 9 of 12 cases. No correlation was noted between the degree of aneusomy and TP53 overexpression. In contrast, HER-2/neu amplification was present in two cases, both with large numbers of aneusomic chromosomes. Amplification of C-MYC was detected in only one case that had a moderate number of numeric abnormalities. In a subset of cases in which premalignant lesions were examined, aneusomy was found to be an early change, frequently present in both Barrett's esophagus and dysplastic regions. In contrast, gene amplification and TP53 overexpression were restricted to more advanced areas of dysplasia and malignancy. Screening larger cohorts of patients with Barrett's esophagus or dysplasia for numeric abnormalities of chromosomes 6, 7, 11, and 12 may determine whether any of these abnormalities are predictive markers of progression to malignancy.
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PMID:Interphase cytogenetics of esophageal adenocarcinoma and precursor lesions. 977 3

We previously found that cases of typical B-chronic lymphocytic leukemia (CLL), atypical B-CLL with t(11;14) and mantle cell lymphomas characterized by rapid progression of the disease and resistance to therapy, had mutations of the TP53 gene. In this paper, abnormalities of the TP53 gene were investigated in two cases of prolymphocytic leukemia, one with t(11;14)(q13;q32), evolving from atypical CLL (patient 1), and one presenting as a de novo condition (patient 2). TP53 DNA was investigated by Southern blot and PCR-SSCP analysis, and TP53 expression was investigated by Northern blot analysis and immunocytochemistry. C-MYC and BCL-1/PRAD1 gene expression were also investigated. Restriction enzyme analysis of TP53 DNA in patient 1 showed alteration of fragments including exon I and intron I, and, in both patients, a specific loss of TP53 DNA. In patient 2, PCR direct sequencing showed in exon VII a 9 bp deletion including codons 252-254. In patient 1, TP53 RNA and protein were not found, indicating that the unusual 5' rearrangement has affected TP53 gene expression. By contrast, patient 2 exhibited detectable TP53 RNA and protein. Detectable but weak BCL-1/PRAD1 RNA was present in both patients, whereas C-MYC RNA expression was clearly present only in case 1. The presence of TP53 hemizygous mutations in both patients suggests that TP53 abnormalities may be important in the pathogenesis of prolymphocytic leukemia (PLL), and may possibly account for the frequent resistance to therapy observed in this disease.
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PMID:5' region and exon 7 mutations of the TP53 gene in two cases of B-cell prolymphocytic leukemia. 984 9

Spontaneous apoptosis was assessed in ten small-cell (SCLC) and five non-small cell (NSCLC) lung carcinoma cell lines by the TUNEL assay and chromatin cleavage. TUNEL staining showed significantly higher apoptotic index (AI) in SCLC (2-20%) compared with NSCLC lines (0.2-1%) in untreated exponentially growing cells. Six out of ten SCLC and none of the NSCLC showed DNA fragmentation when analysed by agarose gel electrophoresis. Field inversion pulse gel electrophoresis was used in a subset of cell lines and showed the presence of high molecular weight fragments in untreated SCLC lines U-1285 and U-1906 cells, but not in the NSCLC line U-1810. Important molecular determinants of apoptosis were studied by Western blot. Bcl-2 was detected at highest level in SCLC. There was no correlation between the ratio Bcl-2/Bax and AI in all tested cell lines. Neither p53 nor c-Myc protein status correlated to AI. Pro-caspase-3 was expressed in all cell lines without correlation to AI and no difference between the SCLC and NSCLC groups was found. In conclusion, this study shows a high degree of spontaneous apoptosis in SCLC lines compared to NSCLC lines unrelated to Bcl-2/Bax ratio.
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PMID:Higher spontaneous apoptotic index in small cell compared with non-small cell lung carcinoma cell lines; lack of correlation with Bcl-2/Bax. 986 2

PCAF histone acetylase is found in a complex with more than 20 associated polypeptides. Here we report cloning and characterization of the 400 kDa PCAF-associated factor referred to as PAF400. PAF400 is almost identical to TRRAP, which binds to c-Myc and E2F, and has significant sequence similarities to the ATM superfamily including FRAP, ATM, ATR, and the catalytic subunit of DNA-PK. Remarkably, PAF400 and FRAP share sequence similarity in broad regions that cover 80% of the entire PAF400 sequence. However, unlike the other members of the ATM superfamily, PAF400 is not a protein kinase as judged from the lack of kinase motif and autophosphorylation activity. We discuss the possibility that PAF400 may play a role in signaling of DNA damage to p53 by stimulation of p53 acetylation.
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PMID:The 400 kDa subunit of the PCAF histone acetylase complex belongs to the ATM superfamily. 988 74

Oxidative stress has long been implicated in the pathogenesis of both the acute and chronic neurotoxic effects of glutamate acting through ionotrophic receptors of the N-methyl-d-aspartate (NMDA) subtype. To evaluate the contribution of oxidative stress to the NMDA receptor-mediated apoptotic death of rat striatal neurons in vivo, the effects of a novel, orally administered free radical scavenger, OPC-14117, was studied following intrastriatal infusion of the NMDA receptor agonist quinolinic acid (QA). Receptor autoradiography and in situ hybridization histochemistry showed that pretreatment with OPC-14117 (600 mg/kg) reduced the QA (120 nmol)-induced loss of striatal D1 dopamine receptors by about 20% (p<0.01) and NMDA receptors by 15% (p<0.01) as well as 67 kDa glutamic acid decarboxylase mRNA (34%; p<0.01) and proenkephalin mRNA (36%; p<0.01). OPC-14117 also decreased the apomorphine-induced ipsilateral rotational response in unilaterally QA-lesioned animals by about 70% (p<0.05). In addition, OPC-14117 pretreatment inhibited QA-induced internucleosomal DNA fragmentation. Western blot analysis and electrophoresis mobility shift assay further revealed that the free radical scavenger (300 and 600 mg/kg) blunted the QA-induced degradation of IkappaBalpha (increased IkappaBalpha levels from about 15% to 33 and 62% of control, respectively; p<0.01) as well as the ensuing activation of NF-kappaB by 25 to 34%, respectively (p<0. 01) and the augmentation in c-Myc (35 to 70%, respectively) and p53 expression by 50-80%, respectively (both p<0.01). In contrast, OPC-14117 had no significant effect on the QA-induced increase in AP-1 binding activity. These results suggest that the NMDA receptor-mediated generation of reactive oxygen species contributes to the QA-induced activation of NF-kappaB and further that orally administered OPC-14117 partially protects against excitotoxin-induced apoptosis of striatal neurons through inhibition of the NF-kappaB apoptotic cascade.
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PMID:Free radical scavenger OPC-14117 attenuates quinolinic acid-induced NF-kappaB activation and apoptosis in rat striatum. 988 20

Loss of p53 function by mutational inactivation is the most common marker of the cancerous phenotype. Previous studies from our laboratory have demonstrated 17 beta estradiol (E2) induction of p53 protein expression in breast cancer cells. Although direct effects of E2 on the expression of p53 gene are not known, the steroid is a potent regulator of c-Myc transcription. In the present studies, we have examined the ability of E2 and antiestrogens to regulate the P1 promoter of the p53 gene which contains a c-Myc responsive element. Estrogen receptor (ER)-positive T47D and MCF-7 cells were transiently transfected with the P1CAT reporter plasmid and levels of CAT activity in response to serum, E2 and antiestrogens were monitored. Factors in serum were noted to be the dominant inducers of chloramphenicol acetyltransferase (CAT) expression in MCF-7 cells. The levels of CAT were drastically reduced when cells were maintained in serum free medium (SFM). However, a subtle ER-mediated induction of CAT expression was detectable when MCF-7 cells, cultured in SFM, were treated with E2. In serum-stimulated T47D cells, the CAT expression was minimal. The full ER antagonist, ICI 182 780 (ICI) had no effect. Treatment with E2 or 4-hydroxy tamoxifen (OHT) resulted in P1CAT induction; OHT was more effective than E2. Consistent with c-Myc regulation of the P1 promoter, E2 stimulated endogenous c-Myc in both cell lines. Two forms of c-Myc were expressed independent of E2 stimuli. The expression of a third more rapidly migrating form was E2-dependent and ER-mediated since it was blocked by the full ER antagonist, ICI, but not by the ER agonist/antagonist OHT. These data demonstrate both ER-mediated and ER-independent regulation of c-Myc and the P1 promoter of the p53 gene, and show differential effects of the two classes of antiestrogens in their ability to induce the P1 promoter of the p53 gene in breast cancer cells.
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PMID:Estrogen-dependent and independent activation of the P1 promoter of the p53 gene in transiently transfected breast cancer cells. 1002 83

Wild-type (wt) p53 frequently induces apoptosis when expressed in tumor cells whereas mutant p53 acts as an oncoprotein and consequently, stimulates cell proliferation. We report here exceptions to that rule. p53 conformational mutant 175H and DNA contact mutant 273H provoke apoptosis in human p53-deficient Hep3B hepatoma cells with delayed kinetics relative to wt p53. Similarly, c-Myc strongly stimulates apoptosis in these cells. In contrast, viral oncoproteins E1A and E7, and the cellular oncoprotein MDM-2, fail to elicit cytocidal responses. Efficient apoptotic cell death by mutant p53 requires oligomerization as 175H and 273H with deletions between amino acid residues 326 and 347 of the oligomerization domain are nontoxic. Apoptosis by mutant or wt p53 was significantly inhibited by the serine protease inhibitor AEBSF but not by the inactive analog AEBSA. Together, these results suggest that a wt p53-independent control mechanism is operational in Hep3B cells that eliminates cells upon sensing illegitimate proliferation signals originating from certain oncoproteins, including mutant p53 and Myc. We suggest that some tumor cell types lack p53 altogether because they tolerate neither wild-type nor mutant forms of the protein.
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PMID:Mutant p53 can provoke apoptosis in p53-deficient Hep3B cells with delayed kinetics relative to wild-type p53. 1003 Jun 75

The sensitivities of apoptosis induced by E1A, c-Myc, Bax, and Nip3 to wild-type (wt) and mutated p53 and Id proteins were analyzed by transient transfection followed by flow cytometry with p53 null mouse cerebellum cell lines W7 and M13 that express wt and mutated p53 in response to dexamethasone, respectively. Apoptosis induced by c-Myc was stimulated weakly by wt p53, strongly by Ids, but suppressed completely by mutated p53 irrespective of coexpression with Ids, while apoptosis induced by E1A was suppressed by mutated p53 but stimulated when coexpressed with Ids. Apoptosis induced by Bax was little affected by wt and mutated p53, but inhibited by Ids, while apoptosis induced by Nip3 was inhibited by both wt and mutated p53 and inhibition was stimulated by Ids. Caspase-1 was activated only by Bax significantly when coexpressed with mutated p53 but not with wt p53. These results indicate that the apoptotic processes elicited by these inducers are different and differently affected by wt and mutated p53 and by Ids.
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PMID:Effects of wild-type and mutated p53 and Id proteins on the induction of apoptosis by adenovirus E1A, c-Myc, Bax, and Nip3 in p53 null mouse cerebellum cells. 1004 78

The ability of p53 to promote apoptosis in response to mitogenic oncogenes appears to be critical for its tumor suppressor function. Caspase-9 and its cofactor Apaf-1 were found to be essential downstream components of p53 in Myc-induced apoptosis. Like p53 null cells, mouse embryo fibroblast cells deficient in Apaf-1 and caspase-9, and expressing c-Myc, were resistant to apoptotic stimuli that mimic conditions in developing tumors. Inactivation of Apaf-1 or caspase-9 substituted for p53 loss in promoting the oncogenic transformation of Myc-expressing cells. These results imply a role for Apaf-1 and caspase-9 in controlling tumor development.
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PMID:Apaf-1 and caspase-9 in p53-dependent apoptosis and tumor inhibition. 1010 18

Deregulated c-Myc expression leads to a cellular state where proliferation and apoptosis are equally favored depending on the cellular microenvironment. Since the apoptotic sensitivity of many cells is influenced by the status of the p53 tumor suppressor gene, we investigated whether the induction of apoptosis by DNA damage or non-genotoxic stress are also influenced by the p53 status of cells with altered c-Myc activity. Rat-1 fibroblasts expressing a conditional c-Myc allele (c-MycER), were transfected to express an antisense RNA complimentary to p53 mRNA. Expression of antisense p53 RNA decreased p53 protein levels and delayed p53 accumulation following c-Myc activation. Under hypoxic or low serum conditions, cells expressing antisense p53 were substantially more resistant to c-Myc-induced apoptosis than were control cells. c-Myc activation also sensitized Rat-1 cells to radiation-induced apoptosis. Rat-1 cells expressing antisense p53 RNA were more resistant to apoptosis induced by the combined effects of c-Myc activation and gamma irradiation. In a similar manner, apoptosis induced by c-Myc in serum starved, hypoxic or gamma irradiated fibroblasts was also inhibited by Bcl-2. These data indicate that p53 is involved in c-Myc-mediated apoptosis under a variety of stresses which may influence tumor growth, evolution and response to therapy.
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PMID:p53 mediates apoptosis induced by c-Myc activation in hypoxic or gamma irradiated fibroblasts. 1020 Apr 56


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