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)

A case of epithelial-myoepithelial carcinoma of the parotid gland harboring p53 mutation is reported. The tumor removed from a 67-year-old Japanese female was composed of an organoid biphasic population of cells: inner dark epithelial cells were surrounded by clear myoepithelial cells. The cells were immunopositive for EMA and smooth muscle actin, respectively. Some of the epithelial cells formed solid nests. Immunostaining for proliferating cell nuclear antigen (PCNA) resulted in a higher percentage of labeled cells in the solid epithelial region than in the region with the more general biphasic pattern. Genetic analysis, including polymerase chain reaction-single strand conformational polymorphism (PCR-SSCP) and nucleotide sequencing, revealed a mutation in codon 207 (aspartic acid to glycine) of the p53 tumor-suppressor gene. To our knowledge, this is the first report of a mutation in the p53 gene in an epithelial-myoepithelial carcinoma of the salivary gland.
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PMID:Epithelial-myoepithelial carcinoma harboring p53 mutation. 1146 4

Adenoviral chimeric tumor suppressor 1 (CTS1) gene transfer was evaluated as a novel approach of somatic gene therapy for malignant glioma. CTS1 is an artificial p53-based gene designed to resist various pathways of p53 inactivation. Here, we report that an adenovirus encoding CTS1 (Ad-CTS1) induces growth arrest and loss of viability in all glioma cell lines examined, in the absence of specific cell cycle changes. In contrast, an adenovirus encoding wild-type p53 (Ad-p53) does not consistently induce apoptosis in the same cell lines. Electron microscopic analysis of Ad-CTS1-infected glioma cells reveals complex cytoplasmic pathology and delayed apoptotic changes. Ad-CTS1 induces prominent activation of various p53 target genes, including p21 and MDM-2, but has no relevant effects on BCL-2 family protein expression. Although Ad-CTS1 strongly enhances CD95 expression at the cell surface, endogenous CD95/CD95 ligand interactions do not mediate CTS1-induced cell death. This is because Ad-CTS1 promotes neither caspase activation nor mitochondrial cytochrome c release and because the caspase inhibitors, z-val-Ala-DL-Asp-fluoromethylketone (zVAD)-fmk or z-Ile-Glu-Thr-Asp- fluoromethylketone (z-IETD)-fmk, do not block CTS1-induced cell death. Ad-CTS1 synergizes with radiotherapy and CD95 ligand in killing glioma cells. In summary, Ad-CTS1 induces an unusual type of cell death that appears to be independent of BCL-2 family proteins, cytochrome c release, and caspases. CTS1 gene transfer is a promising strategy of somatic gene therapy for malignant glioma.
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PMID:Chimeric tumor suppressor 1, a p53-derived chimeric tumor suppressor gene, kills p53 mutant and p53 wild-type glioma cells in synergy with irradiation and CD95 ligand. 1147 23

The tumor suppressor gene p53 has been identified as the most frequent target of genetic alterations in human cancers. Most of these mutations occur in highly conserved regions in the DNA-binding core domain of the p53 protein, suggesting that the amino acid residues in these regions are critical for maintaining normal p53 structure and function. We previously used molecular dynamics calculations to demonstrate that several amino acid substitutions in these regions that are induced by environmental carcinogens and found in human tumors produce certain common conformational changes in the mutant proteins that differ substantially from the wild-type structure. In order to determine whether these conformational changes are consistent for other p53 mutants, we have now used molecular dynamics to determine the structure of the DNA-binding core domain of seven other environmentally induced, cancer-related p53 mutants, namely His 175, Asp 245, Asn 245, Trp 248, Met 249, Ser 278, and Lys 286. The results indicate that all of these mutants differ substantially from the wild-type structure in certain discrete regions and that some of these conformational changes are similar for these mutants as well as those determined previously. The changes are also consistent with experimental evidence for alterations in structure in p53 mutants determined by epitope detectability using monoclonal antibodies directed against these regions of predicted conformational change.
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PMID:Common conformational effects of p53 mutations. 1156 89

Chloroquine is a lysosomotropic agent that causes marked changes in intracellular protein processing and trafficking and extensive autophagic vacuole formation. Chloroquine may be cytotoxic and has been used as a model of lysosomal-dependent cell death. Recent studies indicate that autophagic cell death may involve Bcl-2 family members and share some features with caspase-dependent apoptotic death. To determine the molecular pathway of chloroquine-induced neuronal cell death, we examined the effects of chloroquine on primary telencephalic neuronal cultures derived from mice with targeted gene disruptions in p53, and various caspase and bcl-2 family members. In wild-type neurons, chloroquine produced concentration- and time-dependent accumulation of autophagosomes, caspase-3 activation, and cell death. Cell death was inhibited by 3-methyladenine, an inhibitor of autophagic vacuole formation, but not by Boc-Asp-FMK (BAF), a broad caspase inhibitor. Targeted gene disruptions of p53 and bax inhibited and bcl-x potentiated chloroquine-induced neuron death. Caspase-9- and caspase-3-deficient neurons were not protected from chloroquine cytotoxicity. These studies indicate that chloroquine activates a regulated cell death pathway that partially overlaps with the apoptotic cascade.
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PMID:Chloroquine-induced neuronal cell death is p53 and Bcl-2 family-dependent but caspase-independent. 1158 24

Recent molecular epidemiological studies have identified polymorphisms in the XPD gene that are associated with increased risk of brain gliomas and head, neck, lung, and skin cancers. However, the functional significance of these polymorphic variants in altering cell processes such as cell cycle checkpoints, DNA repair, and apoptosis is uncertain. We have cloned the XPD variants Lys751Gln, Asp312Asn, and Lys751Gln-Asp312Asn into a pcDNA-3.1-expression vector. Using these constructs, we did not find any detectable difference in either in vitro binding with wild-type p53 or in DNA repair proficiency as measured by host cell reactivation assay. We then genotyped 34 different lymphoblastoid cell lines from six Centre d'Etude du Polymorphisme Humaine (CEPH)/Utah pedigree families and a CEPH/French pedigree family for polymorphisms at codons 751 and 312 and assessed their apoptotic response after either UV or ionized radiation exposure. The lymphoblastoid cell lines with homozygous or heterozygous Asp at codon 312 have similar apoptotic rates, whereas cell lines with homozygous Asn at codon 312 showed a 2.5-fold increased response to UV (P = 0.005; Student's t test). This is the first report known to us of a functional polymorphism in a gene involved in DNA damage-induced apoptosis. However, the presence of Lys or Gln at codon 751 did not influence the apoptotic response to UV. The diminished apoptotic response of cells containing the 312 Asp allele could both allow the survival and selective clonal expansion of carcinogen-damaged cells and be a mechanistic explanation for the increased risk of cancer at diverse tissue sites.
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PMID:Functional significance of XPD polymorphic variants: attenuated apoptosis in human lymphoblastoid cells with the XPD 312 Asp/Asp genotype. 1160 76

The p53 tumor suppressor protein regulates centrosome duplication through multiple pathways, and p21(Waf1/Cip1) (Waf1), a major target of p53's transactivation function, has been shown to be one of the effectors. However, it had been unclear whether the p53's Waf1-independent centrosome duplication regulatory pathways require its transactivation function. In human cancers, specific residues of p53 are mutated at a high frequency. These 'hot spot' mutations abrogate p53's transactivation function. If p53 regulates centrosome duplication in a transactivation-independent manner, different 'hot spot' mutants may regulate centrosome duplication differently. To test this, we examined the effect of two 'hot spot' mutants (R175H and R249S) for their centrosome duplication regulatory activities. We found that R175H lost the ability to regulate centrosome duplication, while R249S partially retained it. Moreover, R249S associates with both unduplicated and duplicated centrosomes similar to wild-type p53, while R175H only associates with duplicated, but not unduplicated centrosomes. Since cyclin-dependent kinase 2 (CDK2) triggers initiation of centrosome duplication, and p53 is phosphorylated on Ser 315 by CDK2, we examined the p53 mutants with a replacement of Ser 315 to Ala (A) and Asp (D), both of which retain the transactivation function. We found that S315D retained a complete centrosome duplication activity, while S315A only partially retained it. Moreover, S315D associates with both unduplicated and duplicated centrosomes, while S315A associates with only duplicated, but not unduplicated centrosomes. Thus, p53 controls the centrosome duplication cycle both in transactivation-dependent and transactivation-independent manners, and the ability to bind to unduplicated centrosomes, which is controlled by phosphorylation on Ser 315, may be important for the overall p53-mediated regulation of centrosome duplication.
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PMID:Difference in the centrosome duplication regulatory activity among p53 'hot spot' mutants: potential role of Ser 315 phosphorylation-dependent centrosome binding of p53. 1168 64

Galectin-7 is normally expressed in all types of stratified epithelia, but is significantly down-regulated in squamous cell carcinomas. This protein was recently found to be highly inducible by p53 in a colon carcinoma cell line, DLD-1, and designated as PIG1 (for p53-induced gene 1). We studied transfectants of HeLa and DLD-1 cells ectopically expressing this protein and found that they were more susceptible to apoptosis than control transfectants. This was observed in apoptosis induced by mechanistically distinct stimuli, suggesting that galectin-7 acts on a common point in the apoptosis signaling pathways. Further analyses of actinomycin D-induced apoptosis demonstrated that galectin-7 expression causes enhanced caspase-3 activity and poly(ADP-ribose) polymerase cleavage, and the potentiation of apoptosis by galectin-7 was completely abrogated by a caspase inhibitor, benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone. In addition, galectin-7 transfectants displayed accelerated mitochondrial cytochrome c release and up-regulated JNK activity upon apoptosis induction. Several lines of evidence indicate that the effect on apoptosis is not due to the lectin functioning extracellularly through interactions with cell surface glycoconjugates. In fact, this lectin is found to localize in nuclei and cytoplasm of the transfectants and the transformed keratinocyte line HaCaT. Therefore, galectin-7 is a pro-apoptotic protein that functions intracellularly upstream of JNK activation and cytochrome c release. DNA microarray analysis revealed genes that are differentially expressed between galectin-7 and control transfectants. Some of them are potentially contributory to this lectin's proapoptotic function and these include redox-related genes monoamine oxidase B, ryanodine receptor 2, and glutathione S-transferase Mu 3.
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PMID:Galectin-7 (PIG1) exhibits pro-apoptotic function through JNK activation and mitochondrial cytochrome c release. 1170 6

Regulation of the homeostasis of vascular endothelium is critical for the processes of vascular remodeling and angiogenesis under physiological and pathological conditions. Here we show that doxorubicin (Dox), a drug used in antitumor therapy, triggered a marked accumulation of p53 and induced CD95 gene expression and apoptosis in proliferating human umbilical vein endothelial cells (HUVECs). Transfection and site-directed mutagenesis experiments using the CD95 promoter fused to an intronic enhancer indicated the requirement for a p53 site for Dox-induced promoter activation. Furthermore, the p53 inhibitor pifithrin-alpha (PFT-alpha) blocked both promoter inducibility and protein up-regulation of CD95 in response to Dox. Up-regulated CD95 in Dox-treated cells was functional in eliciting apoptosis upon incubation of the cells with an agonistic CD95 antibody. However, Dox-mediated apoptosis was independent of CD95/CD95L interaction. The analysis of apoptosis in the presence of PFT-alpha and benzyloxycarbonyl-Val-Ala-dl-Asp-fluoromethylketone revealed that both p53 and caspase activation are required for Dox-mediated apoptosis of HUVECs. Finally, Dox triggered Bcl-2 down-regulation, cytochrome c release from mitochondria, and the activation of caspases 9 and 3, suggesting the involvement of a mitochondrially operated pathway of apoptosis. These results highlight the role of p53 in the response of primary endothelial cells to genotoxic drugs and may reveal a novel mechanism underlying the antitumoral properties of Dox, related to its ability to induce apoptosis in proliferating endothelial cells.
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PMID:Doxorubicin induces apoptosis and CD95 gene expression in human primary endothelial cells through a p53-dependent mechanism. 1177 55

The spermine analogue N(1),N(11)-diethylnorspermine (DENSPM) efficiently depletes the cellular pools of putrescine, spermidine and spermine by down-regulating the activity of the polyamine biosynthetic enzymes and up-regulating the activity of the catabolic enzyme spermidine/ spermine N(1)-acetyltransferase (SSAT). In the breast cancer cell line L56Br-C1, treatment with 10 microm DENSPM induced SSAT activity 60 and 240-fold at 24 and 48 h after seeding, respectively, which resulted in polyamine depletion. Cell proliferation appeared to be totally inhibited and within 48 h of treatment, there was an extensive apoptotic response. Fifty percent of the cells were found in the sub-G(1) region, as determined by flow cytometry, and the presence of apoptotic nuclei was morphologically assessed by fluorescence microscopy. Caspase-3 and caspase-9 activities were significantly elevated 24 h after seeding. At 48 h after seeding, caspase-3 and caspase-9 activities were further elevated and at this time point a significant activation of caspase-8 was also found. The DENSPM-induced cell death was dependent on the activation of the caspases as it was inhibited by the general caspase inhibitor Z-Val-Ala-Asp fluoromethyl ketone. The results are discussed in the light of the L56Br-C1 cells containing mutated BRCA1 and p53, two genes involved in DNA repair.
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PMID:Rapid caspase-dependent cell death in cultured human breast cancer cells induced by the polyamine analogue N(1),N(11)-diethylnorspermine. 1184 6

A pleomorphic undifferentiated tumor primarily located in the retroperitoneum with a phenotype compatible with an extraosseous Ewing tumor/peripheral primitive neuroectodermal tumor (ET/pPNET) pattern and unusual molecular features is described. Immunohistochemically, HBA-71 (CD99/mic2) and several neural markers were intensively expressed together with scattered cells expressing carcinoembryonic antigen (CEA). Short-term culture showed biphasic neuroblastic and epithelioid cell populations, with the latter expressing germ cell markers (CEA, alpha-fetoprotein, and the beta-subunit of chorionic gonadotrophin). Conventional cytogenetics displayed several chromosomic rearrangements, especially a complex translocation t(17,2,22,13) (q21::q11-->q33::q12-->q13::q14). These structural abnormalities were confirmed using fluorescence in situ hybridization analysis. Molecular studies revealed EWS-FEV fusion transcripts (exon 7 of the EWS gene and exon 2 of the FEV gene). In addition, a new p53 mutation not previously reported in ET/pPNET involving exon 5 codon 138: GCC to GAC (Ala/Asp) was detected. In our case, we emphasize the presence of atypical features not only from the phenotypic point of view but also at the genetic level as well as the value of detecting such markers in the differential diagnosis with other abdominal pleomorphic tumors.
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PMID:Atypical pleomorphic extraosseous ewing tumor/peripheral primitive neuroectodermal tumor with unusual phenotypic/genotypic profile. 1185 96


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