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)

The etiology of cancer is a complex interplay of various factors, including genetic alterations. Multiple studies have been carried out to identify and characterize mutations that frequently occur during tumorigenesis. In human breast cancer, amplification of proto-oncogenes (c-myc, c-erbB-2/neu) and chromosome 11q13, mutation of p53 and loss of heterozygosity (chromosomes 1, 3p, 6q, 7q, 11p, 13q, 16q, 17, 18q and 22q) represent the major types of genetic abnormalities that have been frequently observed in tumor DNAs. The genetic deletions and mutations could inactivate tumor-suppressor genes. In some studies, specific alterations have been associated with some clinical parameters. Recently, linkage analyses, on large families with a predisposition to breast cancer, have been performed to map putative breast cancer susceptibility genes. The survey of high risk patients should be organised to make an earlier diagnosis.
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PMID:[Molecular analysis of breast cancers: recent developments]. 130 32

Lung cancer arises after a series of morphological changes, which take several years to progress from normal epithelium to invasive cancer. The morphological changes progress from hyperplasia, to metaplasia, to dysplasia, to carcinoma in situ, to invasive cancer and finally to metastatic cancer. Multiple molecular changes have been documented in lung cancers, both small cell (SCLC) and non-small cell (NSCLC) types. The number of changes has been estimated to be in double digits. These changes include activation of dominant oncogenes myc family, (K-ras and neu genes), as well as loss of recessive growth regulatory genes or anti-oncogenes (p53, and RB as well as unidentified gene or genes on chromosome 3). However, cytogenetic and molecular genetic studies indicate that multiple other specific sites of actual or potential DNA loss may be present in lung cancers. Other changes may include development of drug resistance, and production of growth factors and their receptors. It is tempting to associate specific molecular changes with specific morphological changes, as has been attempted in the colon. However, because of the difficulties in serially sampling the respiratory tract, such studies have not been performed to date. Documentation of molecular changes in premalignant lesions and prospective studies of their prognostic effects will be necessary for the design of rational chemoprevention trials.
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PMID:The molecular biology of lung cancer. 130 9

The expression of the protooncogene encoded proteins (c-erbB1, c-erb B2, c-myc, c-fos) and the suppressor gene product p53 was analyzed in 81 human squamous cell carcinomas of the lung and correlated with clinical parameters of the patients (patient survival, presence of metastases and tumor stage) and with biological characteristics of the tumors (tumor growth in nude mice, DNA-ploidy, proliferative activity, drug-resistance and P-glycoprotein or gluathione S-transferase expression). By means of immunohistochemistry, expression of c-erbB1 oncoprotein (EGF-receptor) was detected in 79% of the tumors, c-erbB2 (c-neu) proteins in 35%, c-myc proteins in 48%, c-fos proteins in 41%, and p53 in 43% of the tumors. Patients with c-erbB1 positive tumors had a poor prognosis (p = 0.021). In addition, these tumors were more frequently drug resistant (p = 0.0067). A significant correlation between the growth of the squamous lung carcinomas in nude mice and c-fos oncoprotein expression was demonstrated (p = 0.017). Therefore, EGF-receptor and c-fos products may serve as prognostic factors for the aggressiveness of squamous cell carcinomas of the lung and for the response of these tumors to chemotherapy. No significant correlation was found between the expression of the c-erbB1 or c-fos gene products and stage, metastasis and DNA-ploidy. In contrast to these results, no relationship was found between c-neu or c-myc gene products expression and any of the clinical or biological parameters examined. Aneuploid squamous cell carcinomas of the lung expressed p53 more frequently than diploid tumors (p = 0.027). However, there was no significant difference between p53 expression and stage, survival of patients, metastasis, growth of the tumors in nude mice, proliferative activity and drug-resistance of the tumors.
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PMID:Oncoprotein (c-myc, c-erbB1, c-erbB2, c-fos) and suppressor gene product (p53) expression in squamous cell carcinomas of the lung. Clinical and biological correlations. 134 20

While the activation of the proto-oncogenes has been implicated in the development and progression of cancer of many tissues, the role of oncogenes in the development of oesophageal adenocarcinoma has not been defined. Fifteen patients who had undergone resection for oesophageal adenocarcinoma and 15 who had undergone oesophagectomy or biopsy for Barrett's oesophagus were studied. The latter patients also had adjacent normal gastric mucosa biopsied for comparison with the metaplastic oesophageal mucosa. The mucosal samples were snap frozen and subsequently stained with monoclonal antibodies to the following oncogene associated proteins; c-erbB2 (neu and CE-1) (external domain), c-erbB2 (NCL-CB11) (internal domain), c-src, c-ras, c-myc, c-fos, c-jun, and the onco-suppressor gene--p53. All tumours were well or moderately differentiated adenocarcinomas arising from the lower third of the oesophagus. Eleven specimens showed strong membraneous staining with both c-erbB2 (neu) and c-erbB2 (CBL-CB11). Seven specimens showed strong nuclear staining with p53 onco-suppressor gene. Three specimens were positive for c-ras and c-src, and two were positive for c-jun. In Barrett's epithelium, nine specimens were positive for c-erbB2 (neu and CB11), three were positive for c-src, two were positive for c-ras and c-jun, and one was positive for c-fos. Two of the gastric mucosal biopsy specimens expressed c-erbB2 weakly but no other oncogenes were found. The frequency of positive staining for c-erbB2 is very high, compared with the expression of these genes in other tumours. It is also concluded that errors in the onco-suppressor gene p53, and especially in the external and internal domains of c-erbB2, which is also often expressed in Barrett's mucosa, may be implicated in the development of adenocarcinoma of the oesophagus.
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PMID:Oncogenes and onco-suppressor gene in adenocarcinoma of the oesophagus. 139 27

Transitional-cell carcinoma of the bladder is believed to arise through a series of genetic changes affecting cell growth and proliferation. Two basic types of such genes have been described: protooncogenes and tumor suppressor genes. The former have not been studied extensively in bladder cancer, although there is evidence that c-erb B-2/neu is overexpressed. Loss of specific chromosomal regions, which is common in bladder tumors, may inactivate tumor suppressor genes, of which p53 has received the most attention. Work also has been done on epidermal growth factor and its receptor, yielding evidence that malignant and normal urothelium have different sensitivities to its action. Although several advances must be made before genetic changes come to the clinical forefront, the information now being gained with such speed holds considerable promise for diagnosis and treatment.
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PMID:Molecular genetics and biochemical mechanisms in bladder cancer. Oncogenes, tumor suppressor genes, and growth factors. 144 Oct 21

We examined 100 breast cancers for retinoblastoma (Rb) and p53 protein expression by immunohistochemistry using the PMG3.245 and PAb 1801 antibodies. We assessed percentages of reactive cells and their intensity, as well as staining patterns. The results were correlated with neu protein reactivity and a panel of variables, including age, tumor size and type, nuclear grade, estrogen receptor/progesterone receptor content, and lymph node status. Retinoblastoma protein negativity, either partial or complete, was noted in 47% of cases. Surprisingly, a relatively stronger Rb reaction was seen in some high nuclear grade tumors. p53 positivity was found in 23% of cases and was a significant predictor of Rb loss. p53 also was correlated with poorly differentiated (nuclear grade III) neoplasms and neu expression but not with negative ER status. Tissue distribution profiles for Rb-negative and p53-positive cells were variable in this series, with both uniform and heterogeneous patterns observed. This suggests that Rb and p53 alterations may represent early or late events in transformation. Our findings further implicate Rb and p53 derangements in mammary oncogenesis.
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PMID:Retinoblastoma and p53 gene product expression in breast carcinoma: immunohistochemical analysis and clinicopathologic correlation. 146 76

Intact nuclei derived from poorly or highly liver-metastatic murine large-cell lymphoma cell line RAW117 were digested to discrete subchromatin deoxyribonucleoprotein/ribonucleoprotein (DNP/RNP) complexes with Msp-I. The DNP/RNP complexes were composed of DNP/RNPs which were derived from the DNP/RNP complexes by incubation in the presence or absence of DNase-I and subsequent isolation by two-dimensional [isoelectric focusing/sodium dodecylsulfate (SDS)] polyacrylamide gel electrophoresis (PAGE), electroelution from the gel, and removal of SDS. Approximately 450 DNP/RNPs in the two-dimensional gels corresponding to discrete spots or in some cases streaks were analyzed for the presence of v-abl, p53, c-neu, c-H-ras, beta-casein, 18s rDNA, and mu-chain immunoglobulin genes using a hybridization technique. Ten DNP/RNP complexes contained tightly associated p53 DNA, whereas six contained c- or v-abl, four contained mu-chain gene, two contained c-H-ras, one contained dot-blot beta-casein, two contained 18s rDNA, and c-neu was found in one of the DNP/RNPs. The DNP/RNPs were also analyzed for in vitro RNA polymerase and primase activities. To assess the potential transcription abilities of the isolated DNP/RNPs, individual DNP/RNPs or DNP/RNP mixtures (reconstituted after SDS-PAGE separation) were examined for RNA polymerase initiation and synthesis. When RNA products were formed, these were purified by extracellulose chromatography and used as back-hybridization probes for the genes of interest. The RNA products were also analyzed by RNA gel electrophoresis. RNA formation was inhibitable by actinomycin D, and the RNAs formed ranged in size from approximately 80 kbp to approximately 1 kbp. By mixing various DNP/RNP complexes together, different patterns of RNA synthesis were found. For example, one DNP/RNP of M(r) approximately 140,000, isoelectric point (pl) approximately 5.8 synthesized a high molecular weight RNA in vitro that hybridized with beta-casein cDNA, but beta-casein is not expressed in RAW117 cells, suggesting that the silencing of the beta-casein gene was negated by isolation of the DNP/RNP. Mixing this DNP/RNP with two other specific DNP/RNPs again inhibited the synthesis of beta-casein RNA, suggesting that interactions between DNP/RNP complexes can result in differential RNA expression or regulation of RNA polymerases in vitro.
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PMID:Nucleoproteins derived from subnuclear RNA polymerase complexes of metastatic large-cell lymphoma cells possess transcription activities and regulatory properties in vitro. 146 66

Cesium-137 gamma rays were used to transform rat embryo cells (REC) which were first transfected with activated c-myc or c-Ha-ras oncogenes to produce immortal cell lines (REC:myc and REC:ras). When exposed to 6 Gy of 137Cs gamma rays, some cells became morphologically transformed with focus formation frequencies of approximately 3 x 10(-4) for REC:myc and approximately 1 x 10(-4) for REC:ras, respectively. Cells isolated from foci of gamma-ray-transformed REC:myc (REC:myc:gamma) formed anchorage-independent colonies and were tumorigenic in nude mice, but foci from gamma-ray-transformed REC:ras (REC:ras:gamma) did not exhibit either of these criteria of transformation. Similar to the results with gamma irradiation, we observed a sequence-dependent phenomenon when myc and ras were transfected into REC, one at a time. REC immortalized by ras transfection were not converted to a tumorigenic phenotype by secondary transfection with myc, but REC transfected with myc were very susceptible to transformation by subsequent ras transfection. This suggests that myc-immortalized cells are more permissive to transformation via secondary treatments. In sequentially transfected REC, myc expression was high whether it was transfected first or second, whereas ras expression was highest when the ras gene was transfected secondarily into myc-containing REC. Molecular analysis of REC:ras:gamma transformants showed no alterations in structure of the transfected ras or of the endogenous ras, myc, p53, or fos genes. The expression of ras and p53 was increased in some isolates of REC:ras:gamma, but myc and fos expression were not affected. Similarly, REC:myc:gamma transformants did not demonstrate rearrangement or amplification of the transfected or the endogenous myc genes, or of the potentially cooperating Ha-, Ki-, or N-ras genes. Northern hybridization analysis revealed increased expression of N-ras in two isolates, REC:myc:gamma 33 and gamma 41, but no alterations in the expression of myc, raf, Ha-ras, or Ki-ras genes in any REC:myc transformant. DNA from several transformed REC:myc:gamma cell lines induced focus formation in recipient C3H 10T1/2 and NIH 3T3 cells. The NIH 3T3 foci tested positive when hybridized to a probe for rat repetitive DNA. A detailed analysis of the NIH 3T3 transformants generated from REC:myc:gamma 33 and gamma 41 DNA failed to detect Ha-ras, Ki-ras, raf, neu, trk, abl, fms, or src oncogenes of rat origin.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Rat embryo cells immortalized with transfected oncogenes are transformed by gamma irradiation. 147 53

The accumulation of genetic damage in the forms of activated proto-oncogenes and inactivated tumor-suppressor genes is the driving force in the evolution of a normal cell to a malignant cell. For example, both the activation of ras oncogenes and the inactivation of several suppressor genes, including p53, have been observed in the development of human colon and lung tumors. Point mutations in key codons can activate ras proto-oncogenes and inactivate the p53 suppressor gene. Thus, several critical genes for tumorigenesis are potential targets for carcinogens and radiation that can induce point mutations at low doses. The ras proto-oncogenes are targets for many genotoxic carcinogens. Activation of the ras gene is an early event--probably the "initiating" step--in the development of many chemical-induced rodent tumors. ras Oncogenes are observed in more human tumors and at a higher frequency than any other oncogene, and activation of the proto-oncogene may occur at various stages of the carcinogenic process. Numerous proto-oncogenes other than the ras genes have been shown to be activated in human tumors and to a lesser extent in rodent tumors. Mechanisms that induce aberrant expression of proto-oncogenes are gene amplification and chromosomal translocation or gene rearrangement. Amplification of proto-oncogenes and possibly gene overexpression during the absence of gene amplification occur in the development of many human tumors. For a specific tumor type, amplification of any one proto-oncogene may occur at a low frequency, but the frequency of tumors in which at least one proto-oncogene is amplified can be much higher. Proto-oncogene amplification is usually associated with late stages of tumor progression; however, amplified HER2/neu has been observed in early clinical stages of mammary neoplasia. Activation of proto-oncogenes by chromosomal translocation has been detected at a high frequency in several hematopoietic tumors. Non-ras genes have been detected by DNA transfection assays in both human and rodent tumors. For example, ret and trk genes were found to be activated by gene rearrangements in human papillary thyroid carcinomas. Several potentially new types of oncogenes have also been detected by DNA transfection assays. The etiology of the genetic alterations observed in most human tumors is unclear at present. Examples of ras gene activation and those documented for mutations in the p53 gene demonstrate that exogenous conditions can induce oncogenic mutants of normal genes. The genetic alterations observed in most human tumors are probably generated by both spontaneous events and exogenous conditions.
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PMID:Role of proto-oncogene activation in carcinogenesis. 148 40

The p117 keratinocyte cell line was derived in culture from chemically induced mouse papillomas. The benignly transformed nature of these cells was demonstrated by their ability to re-form benign papillomas when grafted back onto the animal. Retroviral vectors were used to introduce into the p117 cells three distinct oncogenes: v-Ha-ras, p53, and neu. All three oncogenes were able to induce tumorigenic conversion of the p117 keratinocytes when assayed by subcutaneous injection into nude mice. However, grafting the oncogene-transformed cells onto the back of the mouse revealed important differences in the ability of the three oncogenes to induce a fully malignant phenotype. While the ras-transformed papilloma cells formed aggressive carcinomas, p53 and neu transformation yielded an intermediate phenotype, with formation of large exophytic tumors, not yet invasive but with highly dysplastic features remarkably similar to those of in situ carcinomas. These findings establish a homologous, genetically modifiable cell system in which various stages of malignant transformation can be directly compared.
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PMID:Malignant progression of papilloma-derived keratinocytes: differential effects of the ras, neu, and p53 oncogenes. 247 36


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