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)

Examples of practical approaches to molecular epidemiology of human cancer are described. Biomarkers of carcinogen exposure or inherited host factors for cancer susceptibility are discussed. Major advances have been made in the detection of carcinogenmacromolecular adducts through the use of high performance liquid chromatography, immunoaffinity chromatography, the 32P-postlabeling assay, enzyme immunoassays, gas chromatography/mass spectroscopy and synchronous spectrophotofluorimetry. The polycyclic aromatic hydrocarbon-DNA adducts are the most extensively studied in this field and together with antibodies to these adducts found in human serum, they have become useful indicators of exposure to carcinogens. Assays for various kinds of alkyl-DNA adducts have also been developed and the presence of these adducts have been documented in human tissues. Carcinogen-protein adducts have proven to be useful molecular dosimeters of carcinogen exposure. For example, 4-aminobiphenyl hemoglobin adducts are highly correlated with exposure to tobacco smoke. The study of the molecular aspects of interindividual differences in the metabolism and activation of xenobiotics and other genetic markers [DNA-restriction fragment length polymorphisms (RFLPs), mutations, and functional loss of specific genes in carcinogenesis] is an emerging new field that is discussed in the context of genetic susceptibility to cancer. The cytochrome P450 phenotypes and acetylation phenotype are examples of genetic markers that indicate an individual's potential for metabolism of exogenous substances. Further, inherited genetic polymorphic markers, e.g., DNA-RFLPs at protooncogene loci (HRAS-1 and L-myc) have been examined in a case-control study of lung cancer. Data concerning mutations of protooncogenes (H-, K-, and N-RAS) and tumor suppressor genes (retinoblastoma and p53 genes) in various common cancers are providing evidence of multiple genetic lesions that occur during the multistage process of carcinogenesis.
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PMID:Biochemical and molecular epidemiology of cancer. 191 Jun 3

SV40-transformed Chinese hamster C0631 cells pretreated with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) display SV40 DNA amplification. This study shows that following MNNG treatment elevated T antigen synthesis and a 4.5-fold reduction in the extent of its phosphorylation occurred in both pulse-labeled and steady-state-labeled cells. The decrease in phosphorylation was found to be inversely related to carcinogen concentration, i.e. an augmented carcinogen concentration brought about a gradual reduction in T antigen phosphorylation and elevated SV40 DNA amplification. Although the majority of phosphorylation sites on T antigen derived from carcinogen-treated cells were underexpressed, as demonstrated by two-dimensional phosphopeptide mapping, peptide 12 bearing phosphoThrl24, which is known to be essential for DNA replication, was overexpressed. Carcinogen-treated cells showed no changes in p53 synthesis, but it was phosphorylated to a lesser degree. Two-dimensional mapping revealed that the predicted N-terminal major phosphopeptide of p53 extracted from C0631 cells exhibited a lower chromatographic mobility than p53 phosphopeptides from SV40-infected monkey BSC-1 cells. In treated C0631 cells the Rf value of this phosphopeptide was higher than that of control p53. This finding could be ascribed to the failure to phosphorylate the corresponding amino acid residue in this peptide. Moreover, treatment did not affect the halflife of either T antigen or p53 proteins, but caused a dramatic rise in the expression of small t antigen, presumably due to amplification of SV40 DNA.
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PMID:Phosphorylation of T antigen and p53 in carcinogen-treated SV40-transformed Chinese hamster cells. 864 Sep 41

Adducts, formed by carcinogens of tobacco smoke with DNA, can be detected by means of molecular techniques and are used as marker of internal exposure. Carcinogen-DNA adducts produce specific mutations in tumor-suppressor genes (e.g. p53) and oncogenes (e.g. ras), which can be involved in tumor initiation or in later stages of tumor progression (e.g. evolution of an invasive phenotype). Benzo(a)-pyrene, an important carcinogen of tobacco smoke, induces GT transversions, as demonstrated in in vitro systems and animal models. Mutations in the p53- or ras-gene are more common in human tumors of the lung, head and neck, bladder and pancreas in smokers than in non-smokers. Molecular biology of cancer gains increasing significance in clinical practice since 1.) the presence of certain mutations confers an unfavorable prognosis to malignant disease (e.g. ras mutations in lung cancer), 2.) ras and p53 mutations often occur early during tumor development and can thus facilitate diagnosis of malignant disease, and 3.) minimal residual disease can be detected using molecular techniques. After resection of cancer of the head and neck, tumor recurred more frequently in patients with no evidence of residual disease as assessed by pathohistologic criteria than in patients with no evidence of residual disease as evaluated by p53 immunostaining.
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PMID:[Molecular biology of tobacco smoke associated neoplasia]. 901 41

Lung cancer is the most common cause of cancer death in Japanese males, the incidence having increased markedly in recent years. Carcinogen exposure such as to tobacco-smoke and air pollution are associated with the probability of developing lung cancer. Aquired somatic mutations play an important role in the pathogenesis of environmentally induced lung cancers. Cytogenetic and molecular analysis of lung tumors has made it possible to examine this hypothesis and to search for candidate genes that may be targeted by chronic exposure to these carcinogens. Early studies implicate several distinct chromosomal loci (3p, 9p, 13q, 17p, and others) and suggest sequential genetic events occur during the initiation and progression of lung carcinogenesis. Several suppressor genes including Rb (13q), P53 (17p), and P16 (9p) have been identified and cloned at these chromosomal loci. The identification of putative tumor suppressor gene at chromosome 3p is still under work. Understanding the interaction of P53, RB, cyclins, and protein kinase inhibitors including P16 will be essential to the development of the next generation of diagnostic and therapeutic studies for lung cancer.
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PMID:Tumor suppressor genes in human lung cancer. 939 13

A challenging goal of molecular epidemiology is to identify an individual's risk of cancer. Molecular epidemiology integrates molecular biology, in vitro and in vivo laboratory models, biochemistry, and epidemiology to infer individual cancer risk. Molecular dosimetry of carcinogen exposure is an important facet of molecular epidemiology and cancer risk assessment. Carcinogen macromolecular adduct levels, cytogenetic alterations and somatic cell mutations can be measured to determine the biologically-effective doses of carcinogens. Molecular epidemiology also explores host cancer susceptibilities, such as carcinogen metabolism, DNA repair, and epigenetic and genetic alterations in tumor suppressor genes. p53 is a prototype tumor suppressor gene and is well suited for analysis of mutational spectrum in human cancer. The analyses of germline and somatic mutation spectra of the p53 tumor suppressor gene provide important clues for cancer risk assessment in molecular epidemiology. For example, characteristic p53 mutation spectra have been associated with: dietary aflatoxin B1 exposure and hepatocellular carcinoma; sunlight exposure and skin carcinoma; and cigarette smoking and lung cancer. The mutation spectrum also reveals those p53 mutants that provide cells with a selective clonal-expansion advantage during the multistep process of carcinogenesis. The p53 gene encodes a multifunctional protein involved in the cellular response to stress including DNA damage and hypoxia. Certain p53 mutants lose tumor suppressor activity and gain oncogenic activity, which is one explanation for the commonality of p53 mutations in human cancer. Molecular epidemiological results can be evaluated for causation by inference of the Bradford-Hill criteria, i.e. strength of association (consistency, specificity and temporality) and biological plausibility, which utilizes the 'weight of the evidence principle'.
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PMID:Molecular epidemiology of human cancer. 1002 57

A challenging goal of molecular epidemiology is to identify an individual's risk of cancer. Molecular epidemiology integrates molecular biology, in vitro and in vivo laboratory models, biochemistry and epidemiology to infer individual cancer risk. Molecular dosimetry of carcinogen exposure is an important facet of molecular epidemiology and cancer risk assessment. Carcinogen macromolecular adduct levels, cytogenetic alterations and somatic cell mutations can be measured to determine the biologically effective doses of carcinogens. Molecular epidemiology also explores host cancer susceptibilities, such as carcinogen metabolism, DNA repair, and epigenetic and genetic alterations in tumor suppressor genes. p53 is a prototype tumor suppressor gene and is well suited for analysis of mutational spectrum in human cancer. The analyses of germ line and somatic mutation spectra of the p53 tumor suppressor gene provide important clues for cancer risk assessment in molecular epidemiology. For example, characteristic p53 mutation spectra have been associated with: dietary aflatoxin B1 exposure and hepatocellular carcinoma; sunlight exposure and skin carcinoma; and cigarette smoking and lung cancer. The mutation spectrum also reveals those p53 mutants that provide cells with a selective clonal expansion advantage during the multistep process of carcinogenesis. The p53 gene encodes a multifunctional protein involved in the cellular response to stress including DNA damage and hypoxia. Certain p53 mutants lose tumor suppressor activity and gain oncogenic activity, which is one explanation for the commonality of p53 mutations in human cancer. Molecular epidemiological results can be evaluated for causation by inference of the Bradford-Hill criteria, i.e., strength of association (consistency, specificity and temporality) and biological plausibility, which utilizes the "weight of the evidence principle."
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PMID:Molecular epidemiology of human cancer. 1002 91

Once mutated, a single cell must expand into a clone before becoming significant for carcinogenesis. The forces driving clonal expansion and the obstacles that must be overcome are poorly understood. In a genetic mechanism, acquiring a second mutation conferring a proliferative advantage would enable the cell to expand autonomously. If carcinogen exposure instead induced a physiological change, clonal expansion would require the carcinogen's continued presence. To determine which is the case, we studied microscopic clones of keratinocytes mutated in the p53 tumor suppressor gene. Carcinogen exposure was controlled by irradiating mice with 280-320 nm UV radiation (UVB), sunlight's principal carcinogenic component; expansion of mutant clones was observed in epidermal sheets. p53-mutant clones grew only during chronic UVB exposure. Therefore, clonal expansion was not triggered by a proliferative mutation but was instead continually driven by UVB. Unexpectedly, the clone size distribution showed periodicity with maxima at estimated intervals of 16 +/- 6 cells, the size of the epidermal proliferating unit in murine dorsal skin. In the absence of UVB, rare "imprisoned clones" increased in cell number without increasing in area. We conclude that: stem cell compartments act as physical barriers to clonal expansion of a p53-mutant keratinocyte; a rate-limiting step in clonal expansion is the colonization of an adjacent compartment; and sustained UVB enables the p53-mutant keratinocyte to colonize without incurring an additional mutation.
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PMID:Escaping the stem cell compartment: sustained UVB exposure allows p53-mutant keratinocytes to colonize adjacent epidermal proliferating units without incurring additional mutations. 1170 78

The tumor suppressor p53 is regulated in part by binding to cellular proteins. We used p53 as bait in the yeast two-hybrid system and isolated homeodomain-interacting protein kinase 1 (HIPK1) as a p53-binding protein. Deletion analysis showed that amino acids 100-370 of p53 and amino acids 885-1093 of HIPK1 were sufficient for HIPK1-p53 interaction. HIPK1 was capable of autophosphorylation and specific serine phosphorylation of p53. The HIPK1 gene was highly expressed in human breast cancer cell lines and oncogenically transformed mouse embryonic fibroblasts. HIPK1 was localized to human chromosome band 1p13, a site frequently altered in cancers. Gene-targeted HIPK1-/- mice were grossly normal but oncogenically transformed HIPK1 -/- mouse embryonic fibroblasts exhibited reduced transcription of Mdm2 and were more susceptible than transformed HIPK1+/+ cells to apoptosis induced by DNA damage. Carcinogen-treated HIPK1 -/- mice developed fewer and smaller skin tumors than HIPK1+/+ mice. HIPK1 may thus play a role in tumorigenesis, perhaps by means of the regulation of p53 and/or Mdm2.
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PMID:Characterization of cells and gene-targeted mice deficient for the p53-binding kinase homeodomain-interacting protein kinase 1 (HIPK1). 1270 66

It has been firmly established in epidemiological studies that early full-term pregnancy affords lifetime protection against the development of breast cancer. This phenomenon can be mimicked in rat and mouse models of mammary cancer in which the hormones estrogen and progesterone are given for 21 days. Carcinogen-induced proliferation is blocked as a consequence of hormone pretreatment. Among several genes implicated by molecular studies to be differentially expressed is the tumor suppressor gene p53. Both immunohistochemical and Western blot studies indicate that p53 protein expression is increased in hormone-pretreated mice and rats. The p53-regulated gene p21Cip1 is also increased concomitantly with p53. To test directly the causative role of p53 in conferring a protective phenotype, we examined the hormone-induced protective effect in BALB/c p53 null mammary epithelium. In the mammary epithelium, the absence of p53 gene expression abrogated the protective effect of prior pregnancy. The tumor incidence curves were superimposable in p53 null mammary epithelium that were treated with 7,12-dimethylbenzanthracene or pregnancy plus 7,12-dimethylbenzanthracene. These results demonstrate that p53 plays a pivotal role in hormone-induced protection and raises the question of the mechanisms by which the steroid hormones, estrogen and progesterone, functionally activate p53.
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PMID:Breast cancer: the protective effect of pregnancy. 1473 95

A most convenient model to study mechanisms of live organism response to chemical carcinogens is tumor induction in murine liver by aminoazodyes, in particular by ortho-aminoazotoluene (OAT). We studied both early and late stages of hepatocarcinogenesis on several lines of inbred mice differing in sensibility to OAT. By means of autoradiography, we examined proliferative activity of hepatocytes obtained from the liver of sensitive (A/He, DD, SWR) and resistant to OAT AKR, CC57Br, BALB/c lines of mice, which were injected carcinogen. The level of p53, p21Cip1, bax, mdm2, cyclin G, gadd45 genes expression in the liver of mice of different lines given OAT injection was studied by multiplex PCR method. Carcinogen caused a decrease of hepatocyte proliferative activity induced by partial hypatectomy (PHE), and an increase in p53, p21Cip, bax, mdm2, and cyclin G genes within mice of A/He, DD and SWR lines. Cell fusion experiments on hepatocytes obtained from regenerating murine liver sensitive to A/He line carcinogen and given long-time OAT administrations with resting and proliferating fibroblasts of NIH 3T3 mice revealed no obvious suppression of DNA synthesis in heterokaryons. Unlike, in fusion experiments on serum-stimulated fibroblasts with hepatocytes obtained from the liver of BALB/c line mice also given OAT suppression of DNA synthesis in stimulated fibroblasts in heterokaryons was observed 15 days following PHE. These results enable us to conclude that OAT administrations break negative endogenous mechanisms of hepatocyte proliferation control in the liver of mice sensitive to carcinogenes.
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PMID:[Different sensitivity of inbred mice to hepatocarcinogen ortho-aminoazotoluene may be due to differences in the negative control mechanisms of hepatocyte proliferation]. 1534 88


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