Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have established two cell lines of hepatocellular carcinoma [Hep-KANO, clone 1 (CL-1) and clone 2 (CL-2)] from tissue obtained at autopsy of a hepatitis B virus (HBV) carrier without histological signs of hepatitis or liver cirrhosis. These cell lines differed considerably from each other in morphology, proliferation pattern, alpha-fetoprotein secretion, albumin synthesis, cytokine secretion, modal chromosome number and transplantability to nude mice. Histologic examinations also revealed differences between them. Amplification of N-myc, L-myc, H-ras, K-ras, N-ras, c-erb-B and c-erb-B-2 and rearrangement of p53 were not found in either of the cell lines. However, CL-1 and CL-2 showed an identical HBV-DNA integration pattern. A 4-fold amplification of c-myc was observed in CL-1, but not in CL-2. Hep-KANO cell lines, CL-1 and CL-2 may be useful in clarifying the question of whether hepatocarcinogenesis is directly caused by HBV infection.
 ...
PMID:Characteristics of human hepatocellular carcinoma cell lines (Hep-KANO) derived from a non-hepatitic, non-cirrhotic hepatitis B virus carrier. 782 95

Renal cell carcinomas sometimes show sarcomatoid transformation, thus comprising both sarcomatous and carcinomatous components. Such sarcomatoid renal cell carcinomas are highly malignant with pronounced proliferative activity. The present investigation was conducted to assess the mutational status of the p53 and H-ras genes independently in carcinomatous and sarcomatous portions of individual tumors, applying PCR, subcloning, and sequencing to 14 cases. Sarcomatoid portions showed an extremely high mutation rate for the 53 gene (11 of 14, 78.6%) with two mutational hot spots at codons 278 (8 of 14, 57.1%) and 244 (6 of 14, 42.9%). Five cases showed double mutations, four cases had mutations at codons 278 and 244, and one case had mutations at codons 278 and 248. In contrast, the carcinomatous portions demonstrated a low mutation rate for the p53 gene (2 of 14, 14.3%) and no double mutations were detected. Ten cases showed genetic heterogeneity in the p53 gene between the two tumor components. Furthermore, p53 overexpression was immunohistochemically observed only in those components with p53 mutations, mainly in the sarcomatoid portions. No H-ras mutations were observed. The findings strongly suggest that p53 mutations leading to overexpression of p53 protein are closely associated with sarcomatoid transformation in renal cell carcinomas.
 ...
PMID:Mutations of the p53 gene and p53 protein overexpression are associated with sarcomatoid transformation in renal cell carcinomas. 783 36

Although loss of sensitivity to transforming growth factor beta (TGF beta) may be a key step in the escape of epithelial tumours from normal growth control, the intracellular signals determining responsiveness remain controversial, particularly the role of p53. We have investigated this question using thyroid epithelial lines as a model. We analysed (i) human thyroid cancer cell lines having either wild-type (wt) or mutant p53; (ii) rat thyroid lines derived by spontaneous immortalisation following introduction of mutant H-ras, which exhibit high levels of wt p53 but loss of p53-mediated cell-cycle control. Loss of response to TGF beta 1 was found in all human lines bearing mutant p53, and in the majority of the functionally equivalent rat lines, consistent with a role of wt p53 in mediating response. However, introduction of a dominant negative p53 mutant into TGF beta 1 responsive human lines containing wt p53 did not reduce responsiveness, demonstrating that p53 function is not necessary for TGF beta 1 response. On the other hand, expression of a temperature-sensitive (ts) p53 gene in a partially-responsive rat line demonstrated a highly significant modulation of TGF beta response, which fell from 65% inhibition of 3H-thymidine labelling index at 32.5 degrees C (wt p53 conformation) to only 14% at 37.5 degrees C (mutant conformation). The results suggest that p53 and TGF beta generate separate but interacting inhibitory signals, i.e. that p53 modulates but does not mediate TGF beta response. This conclusion explains previous conflicting data and is consistent with current models of cell cycle control by multiple inhibitors of cyclin-dependent kinases.
 ...
PMID:Interaction between p53 and TGF beta 1 in control of epithelial cell proliferation. 783 30

The response to ultra-violet (u.v.) irradiation varies among cells, but commonly involves the rapid increase in expression of one or more transcription factors. The specific roles of this increased expression are largely unknown. We show here that in mouse NIH3T3 cells, Egr-1 expression is increased two-fold 10 min after u.v. irradiation, rises to a maximum (eightfold induction) after about 2 h and then declines. The expression of p53 protein is also strongly induced but is maximal between 2 to 4 h before declining. In contrast, the expression of c-Fos, and C-Jun proteins are only slightly affected by u.v. The Egr-1 response is independent of the growth state of the cells but depends on tyrosine kinase and protein kinase C activities. c-Ha-Ras is also involved in the induction of Egr-1 in u.v. irradiated cells. Evidence presented suggests that the mechanism for the response involves oxidative stress rather than DNA damage. We show that Egr-1 functions in the protection of cells against u.v. damage since NIH3T3 cells that constitutively express antisense Egr-1 and consequently cannot produce an Egr-1 response to u.v., grow at a rate 26% less than similarly irradiated parental cells and 36% less than nonirradiated parental cells. This is the second protective role described for Egr-1.
 ...
PMID:A biological role for Egr-1 in cell survival following ultra-violet irradiation. 784 71

Rat embryo fibroblast clones transformed with the human papillomavirus type 16 E7 gene and the H-ras oncogene (ER clones) fall into two groups on the basis of endogenous p53 genotype, wild type or mutant. We have compared these clones with the aim of indentifying physiological differences that could be attributed to p53 protein function. We show that all ER clones, regardless of p53 gene status, are tumorigenic and metastatic in severe combined immunodeficiency mice. We demonstrate that only the wild-type p53 protein expressed in ER clones is functional on the basis of its site-specific double-stranded DNA-binding activity and its ability to confer a G1 delay on cells following treatment with ionizing radiation. These data indicate that disruption of the p53 growth-regulatory pathway is not a prerequisite for the malignant conversion of rat embryo fibroblasts expressing the E7 gene and mutant ras. Differences in phenotype that were correlated with loss of p53 protein function included the following: serum-independent growth of ER clones in culture, decreased tumor doubling time in vivo, and increased radioresistance. In addition, we demonstrate the p53-dependent G1 checkpoint alone does not determine radiosensitivity.
 ...
PMID:The p53-mediated G1 checkpoint is retained in tumorigenic rat embryo fibroblast clones transformed by the human papillomavirus type 16 E7 gene and EJ-ras. 786 38

Drugs used in anti-cancer chemotherapy are thought to exert their cytotoxic action by induction of apoptosis. Genes have been identified which can mediate or modulate this drug-induced apoptosis, among which are c-myc, p53 and bcl-2. Since expression of oncogenic ras genes is a frequent observation in human cancer, we investigated the effects of the c-H-ras oncogene on anti-cancer drug-induced apoptosis. Apoptosis induced by a 2 h doxorubicin exposure was measured by in situ nick translation and flow cytometry in a rat cell line (R2T24) stably transfected with the c-H-ras oncogene and in a control cell line (R2NEO) transfected only with the antibiotic resistance gene neo. Both cell lines (R2T24 and R2NEO) had nearly identical growth characteristics, including cell doubling time, distribution over the cell cycle phases and plating efficiency in soft agar. Doxorubicin exposure of the R2NEO cells led to massive induction of apoptosis. In contrast, R2T24 cells, expressing the c-H-ras oncogene, showed significantly less apoptosis after doxorubicin incubation. Doxorubicin induced approximately 3- to 5-fold less cytotoxicity in the R2T24 cells than in the R2NEO cells, as determined by clonogenic assay in soft agar. No difference was observed in intracellular doxorubicin accumulation between the two cell lines, indicating that the classical, P-glycoprotein-mediated multidrug resistance phenotype is not involved in the observed differences in drug sensitivity. In conclusion, our data show that constitutive expression of the c-H-ras oncogene suppresses doxorubicin-induced apoptosis and promotes cell survival, suggesting that human tumours with ras oncogene expression might be less susceptible to doxorubicin treatment.
 ...
PMID:Constitutive expression of the c-H-ras oncogene inhibits doxorubicin-induced apoptosis and promotes cell survival in a rhabdomyosarcoma cell line. 788 Jul 39

The observation that oncogenes are frequently activated in human tumours raises the question of whether these genes are involved in chemical carcinogenesis. H-ras activation is probably an initiating event in mouse skin and rat mammary gland systems. The H-ras oncogene is also important in mouse liver tumours; in mouse lung the K-ras gene is commonly activated. In both, the mutations observed are usually those predicted from the adduct-forming properties of the carcinogen. Among non-ras oncogenes, only raf and neu have been detected in experimental tumours. Tumour suppressor genes are frequently inactivated in human tumours. Searches for such phenomena in animal tumours have generally had disappointing results. p53 and Rb gene alterations are rarely observed in chemically-induced tumours. The reason may be that unknown tumour suppressor genes are involved in animal tumour development. Several novel genes have been identified using animal tumour susceptibility models. Thus, ras genes are important in chemical carcinogenesis, but as the methodology for studying other genes improves, their roles will be seen in perspective.
 ...
PMID:Molecular aspects of chemical carcinogenesis: the roles of oncogenes and tumour suppressor genes. 790 Jan 59

We have investigated point mutations of codons 12, 13, and 61 in H-, K-, and N-ras oncogenes as well as p53 tumour suppressor gene exon 5 through exon 9 by PCR-SSCP analysis in 26 skin biopsy tissues from 16 arsenic-related Bowen's disease patients and 6 skin samples from 4 paraquat manufacturing workers. No mutation was found. These results are different from findings with UV associated skin cancers. Interestingly, a silent change at codon 27 of H-ras in one allele was detected in all 4 paraquat manufacturing workers and in 2 of 16 arsenic-related Bowen's disease patients. It is likely that the molecular mechanisms involved in arsenic and paraquat induced skin cancers differ from sunlight-related skin malignancies.
 ...
PMID:Arsenic-related Bowen's disease and paraquat-related skin cancerous lesions show no detectable ras and p53 gene alterations. 795 56

Rat experimental models using N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) as an initiating agent have been widely used to study carcinogenic processes in the urinary bladder. In this study, early neoplastic lesions from 10 male F344 rats treated with 0.05% BBN for 16 weeks were analyzed for changes in the H-ras or p53 genes by polymerase chain reaction (PCR)-single strand conformation polymorphism (SSCP) analysis and subsequent DNA sequencing. Lesions were pooled for each of the 10 rats and six showed point mutations in the p53 gene and one in the H-ras gene. These results would indicate that BBN-induced rat urinary bladder carcinomas are similar to human urinary bladder carcinomas with respect to alterations in the p53 and H-ras genes and that p53 gene alterations are relatively early events in rat urinary bladder carcinogenesis induced by BBN treatment.
 ...
PMID:p53 mutations in early neoplastic lesions of the urinary bladder in rats treated with N-butyl-N-(4-hydroxybutyl)nitrosamine. 795 81

In this report, we describe the isolation and characterization of six murine squamous cell carcinoma cell lines (BPCC) derived from carcinomas produced by a complete carcinogenesis protocol with benzo[a]pyrene (B[a]P). All six cell lines were tumorigenic to varying degrees in nude mice, and several were spontaneously metastatic to the lungs. The in vivo invasive potential of each BPCC cell line was determined using de-epithelialized tracheal xenotransplants into which cells were inoculated. This assay revealed positive association of tumor grade with in vivo invasiveness, yet no clear relationship to the spontaneous metastatic potential of the cell lines, suggestive that invasive potential is only one determinant of the overall metastatic phenotype. At the molecular level, all six BPCC cell lines revealed the absence of mutations in the H-ras oncogene and no amplification or rearrangement in the cycl 1/cyclin D1 putative oncogene. Analysis of the p53 tumor suppressor gene revealed a direct correlation between positive nuclear immunohistochemical staining of the p53 protein in four BPCC cell lines and the presence of p53 mutations identified by direct sequence analysis. The localization of mutations to exons 7 and 8 of the p53 gene and the detection of G to T transversions in two of the four cell lines bearing p53 mutations are in agreement with previous analyses of a large series of primary B[a]P-induced murine skin tumors. In addition, frameshift mutations were identified in two cell lines. The correlation of the biological and molecular properties of these BPCC cell lines with the known characteristics of primary squamous cell carcinomas induced by B[a]P indicates that these cell lines could be useful tools in elucidating the mechanisms of tumorigenesis of this important chemical carcinogen.
 ...
PMID:Murine squamous cell carcinoma cell lines produced by a complete carcinogenesis protocol with benzo[a]pyrene exhibit characteristic p53 mutations and the absence of H-ras and cyl 1/cyclin D1 abnormalities. 805 40


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>