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)

Meningiomas arise from the arachnoidal cells surrounding the brain and are one of the most common tumors of the central nervous system. These tumors are known to be hormonally modulated and may occur in association with breast carcinoma. Overexpression of the erbB-2 oncogene product and mutation of the tumor suppressor p53 gene are considered causal driving forces in the pathogenesis of adenocarcinomas of the breast. To determine whether abnormal expression of these genes also plays a role in the pathogenesis of meningiomas, we analyzed the expression of the erbB-2 and p53 proteins in 17 atypical and 35 typical meningioma tissue specimens by immunohistochemistry. The staining intensity was assigned a relative value of 0 to 5+, where 5+ denoted confluent immunoreactivity, 4+ to 1+ denoted varying degrees of focal positivity, and 0 denoted no evidence of staining. Levels of p53 and erbB-2 immunohistochemical staining were then correlated with tumor histology. For p53 immunoreactivity, typical meningiomas had a median staining score of 1.0, compared to 4.0 for atypical meningiomas (P < 0.0001, Mann-Whitney U test). For erbB-2 immunoreactivity, typical meningiomas had a median staining score of 5.0 compared to 1.0 for atypical meningiomas (P < 0.0001, Mann-Whitney U test). The inverse relationship between levels of erbB-2 and p53 immunoreactivity was found to be statistically significant (P < 0.0001, ANOVA). Expression of the erbB-2 protein was not associated with gene amplification or the presence of activating mutation in the transmembrane region of the protein. These findings may improve our understanding of the molecular events that occur in the neoplastic transformation of meningothelial cells. The patterns of erB-2 and p53 immunoreactivity may prove to be useful markers with which to identify potentially more malignant meningiomas.
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PMID:Immunohistochemical evaluation of erbB-2 and p53 protein expression in benign and atypical human meningiomas. 869 33

Chromosomal instability and persistent reproductive cell death show a significant correlation after cells are exposed to ionizing radiation. To examine the possible role of apoptosis in persistent reproductive cell death, we analyzed subsets of chromosomally stable and unstable clones for relationships between chromosome stability, reproductive integrity, and apoptosis. All clones were generated from the GM10115 cell line and derived from single progenitor cells surviving 10 Gy of X-rays, and all measurements were made approximately 60-80 generations after irradiation. The incidence of apoptosis, as measured by both annexin V binding of phosphatidylserine residues and terminal deoxynucleotidyl transferase labeling of DNA strand breaks, was significantly higher in chromosomally unstable clones than it was in chromosomally stable clones (P < 0.05; ANOVA and Student's t test). Furthermore, statistical analyses of the biological end points of persistent reproductive cell death and apoptosis were consistent, showing R2 values of 0.78 and 0.76, respectively. These results suggest that persistent reproductive cell death can, in part, be explained by the predisposition of a fraction of the clonal population to undergo apoptosis or necrosis. Immunological blot analyses of protein levels and DNA bandshift assays confirmed the mutant status of p53 in the host cell line, implying an apoptotic pathway that is independent of p53. Induction of apoptosis by agents such as actinomycin D, etoposide, and staurosporine and induction of necrosis by sodium azide were accompanied by an increase in the level of intracellular peroxy radicals and lipid peroxidation products, two independent end points that are typically associated with oxidative stress. Similar findings were observed in several subclones showing persistent apoptosis. These results suggest that the elevated levels of free radical damage that we detected were derived from the fraction of cells dying by apoptotic or necrotic processes. Possible mechanisms whereby oxidative stress may contribute indirectly to the perpetuation of chromosomal instability are discussed.
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PMID:Apoptosis, reproductive failure, and oxidative stress in Chinese hamster ovary cells with compromised genomic integrity. 972 83

In this study, expressions of cell-cycle-related genes: p53, retinoblastoma (Rb), p21, bcl-2(alpha), bcl-2(beta); protooncogene c-ski; glial cell marker protein gene S100beta; neurotransmitter gene, substance P and sexual-differentiation-related genes, androgen receptor (AR) and estrogen receptor beta (ER(beta)), are studied in the olfactory bulb of groups of both six female and six male rats at the ages of 3, 10, 20 and 40 days. Expressions of housekeeping genes such as beta-actin, cyclophilin and proliferating cell nuclear antigens (PCNA) are determined using reverse transcription polymerase chain reaction (RT-PCR) for the correction of unequal amount of cDNA added into the samples. Using labeled 32P-dCTP and Phosphorimager technology, relative abundance of radioactivities of the PCR products is obtained by dividing the radioactivity of each individual sample by the corresponding radioactivities of different housekeeping genes. Data evaluated by Two-way ANOVA indicate that only the bcl-2(alpha) gene expression is affected significantly by age, sex and their interactions no matter which of the three housekeeping genes is used for correction. When beta-actin was used for corrections, effects of age but not sex were found in the expressions of p53, Rb, p21, AR, ER(beta), substance P and S100beta genes, but not in bcl-2(beta), c-ski, cyclophilin and PCNA genes. While cyclophilin was used for corrections, only the p53, Rb, AR, ER(beta), substance P and S100beta but not the bcl-2(beta), p21, c-ski, PCNA and beta-actin genes are affected by age. They are all not influenced by sex of the animals. Only the AR, ER(beta) and S100beta genes are age-dependent when PCNA was used for the correction. The other gene expressions are not altered by sex, while the interactions of age and sex were found to be significantly affecting the bcl-2(beta) gene expression. Conclusively, developmental changes of the p53, Rb, AR, ER(beta), substance P and S100beta genes expressions are quite evidenced while only the bcl-2(alpha) gene seems to change significantly during the sexual differentiation of olfactory bulb in rats.
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PMID:Gene expressions during the development and sexual differentiation of the olfactory bulb in rats. 1067 68

The major focus of intrahepatic arterial (IHA) administration of adenoviruses (Ad) has been on safety. Currently, there is little published data on the biological responses to Ad when administered via this route. As part of a Phase I study, we evaluated biological responses to a replication-defective adenovirus encoding the p53 transgene (SCH 58500) when administered by hepatic arterial infusion to patients with primarily colorectal cancer metastatic to the liver. In analyzing biological responses to the Ad vector, we found that both total and neutralizing Ad antibodies increased weeks after SCH 58500 infusion. The fold increase in antibody titers was not dependent on SCH 58500 dosage. The proinflammatory cytokine interleukin-6 (IL-6) transiently peaked within 6 h of dosing. The cytokine sTNF-R2 showed elevation by 24 h post-treatment, and fold increases were directly related to SCH 58500 doses. Cytokines TNF-alpha, IL-1beta, and sTNF-R1 showed no increased levels over 24 h. Predose antibody levels did not appear to predict transduction, nor did serum Ad neutralizing factor (SNF). Delivery of SCH 58500 to tumor tissue occurred, though we found distribution more predominantly in liver tissues, as opposed to tumors. RT-PCR showed significantly higher expression levels (P<0.0001, ANOVA) for adenovirus type 2 and 5 receptor (CAR) in liver tissues, suggesting a correlation with transduction. Evidence of tumor-specific apoptotic activity was provided by laser scanning cytometry, which determined a coincidence of elevated nuclear p53 protein expression with apoptosis in patient tissue. IHA administration of a replication defective adenovirus is a feasible mode of delivery, allowing for exogenous transfer of the p53 gene into target tissues, with evidence of functional p53. Limited and transient inflammatory responses to the drug occurred, but pre-existing immunity to Ad did not preclude SCH 58500 delivery.
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PMID:Biological activities of a recombinant adenovirus p53 (SCH 58500) administered by hepatic arterial infusion in a Phase 1 colorectal cancer trial. 1608 81

In this study, proliferating cell nuclear antigen (PCNA) and p53 protein expressions were analyzed in 16 cases of ameloblastoma and 8 cases of adenomatoid odontogenic tumor (AOT). The cases of ameloblastoma consisted of solid type tumors and histologic arrangements of different subtypes were observed. In some specimens, more than one histologic subtype was identified in the same lesion, and each tumor was categorized according to the predominant cell pattern. The odontogenic tumors were grouped as follows: follicular ameloblastoma (n=7), plexiform ameloblastoma (n=4), acanthomatous + follicular ameloblastoma (n=3), basal cell ameloblastoma (n=2), adenomatoid odontogenic tumor (n=8). PCNA immunohistochemical expression revealed stronger quantitative labeling index for the follicular ameloblastoma, while for p53 protein the strongest quantitative labeling index was detected in the plexiform type. Nevertheless, statistical analysis using ANOVA and Tukey's test did not detect significant differences (p>0.05) among the histologic subtypes of ameloblastoma. The findings of this study suggest that the different histologic patterns of ameloblastoma did not show a direct correlation with their clinical behavior and consequently with the prognosis of the cases. The results also indicated that the ameloblastoma has greater proliferative potential than the AOT, which can contribute to explain its more aggressive and invasive characteristics.
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PMID:Proliferating cell nuclear antigen (PCNA) and p53 protein expression in ameloblastoma and adenomatoid odontogenic tumor. 1611 35

Pulmonary epithelium is known to undergo a preneoplastic process prior to the development of lung carcinoma. Squamous dysplasia and atypical adenomatous hyperplasia have been identified and classified as preinvasive lesions of squamous cell carcinoma and peripheral pulmonary adenocarcinoma, respectively. However, these commonly recognized preinvasive lesions do not completely explain the development of all histological types of lung carcinoma. By examining 114 resection lung specimens, we concluded that there are four histological patterns of bronchial epithelial dysplasia based on morphological features (basal cell dysplasia, columnar cell dysplasia, bronchial epithelial dysplasia with transitional differentiation, and squamous dysplasia). The histological patterns were further characterized by immunohistochemistry. Basal cell dysplasia was focally positive for cytokeratin (CK) 17 and 10/13; columnar cell dysplasia was generally positive for CK7, 8, and 18; bronchial epithelial dysplasia with transitional differentiation had a heterogeneous immunoprofile, while squamous dysplasia was positive for CK10/13 and focally positive for CK17. Various degrees of abnormal expression of p53 and Ki-67 were found in the different types of bronchial epithelial dysplasia. The cases were divided into three groups based on degree and extent of bronchial epithelial dysplasia. By Crosstabs McNemar test, the Mann-Whitney U-test (for two independent groups), the Kruskal-Wallis one-way nonparametric ANOVA (for >2 independent groups) and Spearman correlation analysis, the degree and extent of bronchial epithelial dysplasia was shown to be positively correlated with the incidence of bronchogenic carcinoma and multifocal primary lung carcinoma (P<0.05). These findings indicated the following: (1) bronchial epithelium can develop various patterns of dysplasia with abnormal/ambiguous cell differentiation and abnormal expressions of p53 and Ki-67. Thus, these bronchial epithelial dysplastic lesions may represent a preneoplastic process. (2) The degree of bronchial epithelial dysplasia may significantly predispose individuals to bronchogenic carcinoma and multifocal primary lung carcinoma.
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PMID:Histological types and significance of bronchial epithelial dysplasia. 1641 91

Cyclin D3 deregulation has recently been reported in bladder cancer but its prognostic significance remains uncertain. A cohort of 159 patients with stage Ta or T1 primary bladder tumours was investigated to determine the significance of cyclin D3 expression in association with other G1-S phase regulators of the cell cycle (p53, p21Waf1, p27kip1, cyclin D1), including tumour proliferation (ki67-MIB1); its association with conventional clinicopathological parameters; and the relationship between cyclin D3 and loss of heterozygosity (LOH) at the 9p21 (p16INK4a locus) chromosome region. The end point of the study was progression-free survival. Cyclin D3, other G1-S phase regulators, and tumour proliferation were investigated by immunohistochemistry and measured by the grid-counting method. To validate the immunohistochemical expression, cyclin D3 was additionally assessed by western blotting in selected cases. LOH at the 9p21 chromosome region (marker D9S171) was assessed in 125 cases using an AB Prism 310 genetic analyser and a set of microsatellite fluorescence-labelled primers. Cyclin D3 overexpression was related to larger tumour size (>5 cm; p < 0.0001) and high tumour proliferation (>10%; p = 0.025). Mean cyclin D3 expression increased with 2004 WHO grading categories in stage Ta (p = 0.035, ANOVA) and stage T1 (p = 0.047, t test) tumours. Cyclin D3 was not related to other clinicopathological parameters, G1-S phase modulators, or 9p21 LOH. Cox's multivariate analysis selected cyclin D3 as an independent predictor of progression-free survival (p = 0.0012, relative risk (RR) = 5.2366) together with tumour size (p = 0.0115, RR = 4.4442) and cyclin D1 (p = 0.0065, RR = 3.3023). Cyclin D3 expression had the highest risk ratio. Our results suggest that expression of cyclin D3 is relevant to the progression-free survival of patients with Ta/T1 bladder carcinomas.
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PMID:Cyclin D3 expression in primary Ta/T1 bladder cancer. 1648 99

Expression of PERP (p53 apoptosis effector related to PMP-22) was investigated in primary uveal melanomas and its variation was analyzed in relation to clinico-pathological and cytogenetical characteristics of these tumors. The transcriptional level of PERP gene was measured by quantitative real-time RT-PCR in 26 uveal melanomas with known chromosomes 3 and 8 status. PERP protein levels were assessed by Western blot analysis of 22 fresh-frozen tumors and by immunohistochemical analysis of 16 paraffin-embedded tumor specimens. Differential expression of PERP was identified in primary choroidal melanoma specimens, both at transcriptional and protein level. Reduced PERP mRNA level was significantly associated with monosomy 3 (two-way ANOVA and t-test, p=0.004) but not with gains in chromosome 8. Transcriptional downregulation of PERP did not present a statistically significant association with ciliary body involvement, size, PAS-positive loops or cell type. Immunoblotting and immunohistochemistry further demonstrated significantly reduced PERP protein level in monosomy 3 melanomas, as compared with disomy 3 tumors. The altered expression of PERP highlighted this apoptosis-specific target of p53 as a possible contributor to apoptosis in uveal melanoma with PERP downregulation being particularly relevant to the aggressive (monosomy 3) type of uveal melanoma. As PERP is a novel type of p53 effector that is likely to stimulate apoptosis through a mechanism distinct from that of Bcl-2-related mitochondrial effectors, further elucidation of its role in uveal melanoma pathogenesis will assist in the design of novel therapeutic approaches aimed at increasing the rate of apoptosis in this tumor.
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PMID:Expression of p53-induced apoptosis effector PERP in primary uveal melanomas: downregulation is associated with aggressive type. 1678 42

In response to DNA damage, cell cycle arrest, apoptosis, and DNA repair are mediated by a TP53 pathway that induces p21(WAF1/Cip1). The chemotherapeutic drug cis-diamminedichloroplatinum-II (cisplatin) damages cellular DNA by forming cis-diammineplatinum-N(7)-d[GpG] and cis-diammine-platinum-N(7)-d[ApG] adducts. To investigate the role of p21, skin keratinocytes from p21(WAF1/Cip1) wild-type (+/+), heterozygous (+/-), and null (-/-) mice, cultured in calcium levels designed to maintain a proliferating state, were exposed to 5 microM cisplatin continuously for 0, 8, 24, 48 and 72 h. At all time points the (+/-) cells had the fewest Pt-DNA adducts, and at 24 h mean Pt-DNA adduct levels were 541, 153 and 779 fmol adduct/mug DNA for p21(WAF1/Cip1) (+/+), (+/-) and (-/-) cells, respectively [P < 0.05 for (+/+) versus (+/-) and (-/-) versus (+/-)]. In order to understand underlying events, we examined p21(WAF1/Cip1) messenger RNA (mRNA), cell cycle arrest, and apoptosis in these cells. At 48 h of cisplatin exposure p21(WAF1/Cip1) mRNA expression was 2-fold higher in the (+/+) cells, compared to the (+/-) cells. At 24 h, the % of cells in S-phase in cisplatin-exposed cultures, compared to unexposed cultures, was decreased by 51, 40 and 11% in p21(WAF1/Cip1) (+/+), (+/-) and (-/-) cells, respectively (P = 0.04, ANOVA). At 24, 48 and 72 h the % of cisplatin-exposed (+/+) cells in apoptosis was 9.4-10.5%, while the cisplatin-exposed (+/-) and (-/-) cells had 1.2-3.7% of cells in apoptosis. The data support the interpretation that DNA replication arrest and apoptosis do not completely explain the low levels of Pt-DNA adducts in the (+/-) cells, and suggest that p21(WAF1/Cip1) controls activity resulting in either low Pt-DNA adduct formation or enhanced Pt-DNA adduct removal.
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PMID:Cisplatin-DNA damage in p21WAF1/Cip1 deficient mouse keratinocytes exposed to cisplatin. 1715 20

Previous studies have used particle mass and size as metrics to link airborne particles with deleterious health effects. Recent evidence suggests that particle composition can play an important role in PM-toxicity; however, little is known about the specific participation of components (individually or acting in groups) present in such a complex mixture that accounts for toxicity. This work explores relationships among PM(10) components in order to identify their covariant structure and how they vary in three sites in Mexico City. Relationships between PM(10) with cell toxicity and geographical location were also explored. PM(10) was analyzed for elemental composition, organic and elemental carbon, endotoxins and the induction of inhibition of cell proliferation, IL-6, TNFalpha and p53. PM(10) variables were evaluated with principal component analysis and one-way ANOVA. The inhibition of cell proliferation, IL-6 and TNFalpha were evaluated with factorial ANOVA and p53 with the Welch test. The results indicate that there is heterogeneity in particle mass, composition and toxicity in samples collected at different sites. Multivariate analysis identified three major groups: (1) S/K/Ca/Ti/Mn/Fe/Zn/Pb; (2) Cl/Cr/Ni/Cu; and (3) endotoxins, organic and elemental carbon. Groups 1 and 3 showed significant differences among sites. Factorial ANOVA modeling indicated that cell proliferation was affected by PM concentration; TNFalpha and IL-6 by the interaction of concentration and site, and p53 was different by site. Radial plots suggest the existence of complex interactions between components, resulting in characteristic patterns of toxicity by site. We conclude that interactions of PM(10) components determine specific cellular outcomes.
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PMID:Relations between PM10 composition and cell toxicity: a multivariate and graphical approach. 1718 38


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