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 genetic basis of disease susceptibility can be studied by several means, including research on animal models and epidemiological investigations in humans. The two methods are infrequently used simultaneously, but their joint use may overcome the disadvantages of either method alone. We used both approaches in an attempt to understand the genetic basis of aflatoxin B(1) (AFB(1))-related susceptibility to hepatocellular carcinoma (HCC). Ingestion of AFB(1) is a major risk factor for HCC in many areas of the world where HCC is common. Whether humans vary in their ability to detoxify the active intermediate metabolite of AFB(1), AFB(1)-exo-8,9-epoxide, is not certain but may explain why all exposed individuals do not develop HCC. To determine whether human variability in detoxification may exist, in a study of 231 HCC cases and 256 controls, we genotyped eleven loci in two families of AFB(1) detoxification genes; the glutathione S-transferases (GSTs) and the epoxide hydrolases (EPHX). After adjustment for multiple comparisons, only one polymorphism in the epoxide hydrolase family 2 locus remained significantly associated with HCC (odds ratio = 2.06, 95% confidence interval = 1.13-3.12). To determine whether additional susceptibility loci exist, we developed a mouse model system to examine AFB(1)-induced HCC. Susceptibility of 7-day-old mice from two common inbred strains (C57BL/6J, DBA/2J) was assessed. DBA/2J animals were 3-fold more sensitive to AFB(1)-induced HCC and significantly more sensitive to AFB(1) acute toxicity than were C57BL/6J animals. Analysis of the xenobiotic metabolizing genes in the two strains revealed single nucleotide polymorphisms in three genes, Gsta4, Gstt1, and Ephx1. Although the GSTT1 and EPHX1 loci did not appear to be related to HCC in the total population of the human study, a polymorphism in GSTA4 was significantly related to risk in the male subset. The mouse model also demonstrated that absent or compromised p53 was not necessary for the development of carcinogenesis. These results indicate that the comparison of results from human studies and the AFB(1)-susceptible mouse model may provide new insights into hepatocarcinogenesis.
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PMID:Susceptibility to aflatoxin B1-related primary hepatocellular carcinoma in mice and humans. 1290 37

Although little is understood of the underlying mechanisms, there are tissue-specific responses to tumourigenic and therapeutic agents and these responses are influenced by genetic factors. Ionizing radiation is an important tumourigenic and therapeutic agent for which there is substantial evidence for such tissue-dependent and genotype-dependent responses. Because the p53 tumour suppressor protein is a major determinant of cellular responses to radiation, the present study has investigated whether modification of the p53 pathway contributes to tissue-dependent and genotype-dependent responses using inbred strains of mice. Comparison of responses in haemopoietic and epithelial cells in irradiated C57BL/6 and DBA/2 mice revealed significant differences in p53 and apoptotic responses in different cell types and in different cells of the same type, reflecting the complexity of damage responses operating in the whole organism. The data suggest that p53-mediated up-regulation of Bax is a major determinant of apoptosis in the spleen, but not in the intestine, whereas p53-mediated induction of p21(waf1) plays an anti-apoptotic role in the spleen, but not in the intestine. It is also shown that p53 stabilization and differential transactivational activities towards Bax or p21(waf1) are influenced by genetic factors that act in a tissue-specific manner. Analysis of ATM, a potential mediator of differential p53 activation, indicates that this key regulator of radiation responses is preferentially induced in epithelial cells, but is unlikely to account for genetic modification of p53 or apoptotic responses in the mouse strains studied. Polymorphisms in the p53 or DNA-PKcs genes are also unlikely to account for the genetic modifications that are reported here. There are numerous further potential modifiers of the p53 pathway, but analysis of backcross and inter-cross mice demonstrates that genes responsible for the complex modification of these in vivo responses can be identified by linkage analysis. This approach has the potential to reveal new or unexpected interactions involving the p53 pathway that determine both short-term and long-term effects of radiation exposure and the basis of tissue-specific responses and tumour susceptibility.
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PMID:Tissue-specific p53 responses to ionizing radiation and their genetic modification: the key to tissue-specific tumour susceptibility? 1459 49

Susceptibility to mouse plasmacytomagenesis is a complex genetic trait controlled by several Pctr loci (Pctr1, Pctr2, etc). Congenic strain analysis narrowed the genetic interval surrounding the Pctr2 locus, and genes identified in the interval were sequenced from susceptible BALB/c and resistant DBA/2 mice. Frap (FKBP12 rapamycin-associated protein, mTOR, RAFT) was the only gene differing in amino acid sequence between alleles that correlated with strain sensitivity to tumor development. The in vitro kinase activity of the BALB/c FRAP allele was lower than the DBA/2 allele; phosphorylation of p53 and PHAS1/4EBP1 (properties of heat and acid stability/eukaryotic initiation factor 4E-binding protein) and autophosphorylation of FRAP were less efficient with the BALB/c allele. FRAP also suppressed transformation of NIH 3T3 cells by ras, with DBA/2 FRAP being more efficient than BALB/c FRAP. Rapamycin, a specific inhibitor of FRAP, did not inhibit growth of plasmacytoma cell lines. These studies identify Frap as a candidate tumor suppressor gene, in contrast to many reports that have focused on its prooncogenic properties. Frap may be similar to Tgfb and E2f in exerting both positive and negative growth-regulatory signals, depending on the timing, pathway, or tumor system involved. The failure of rapamycin to inhibit plasma cell tumor growth suggests that FRAP antagonists may not be appropriate for the treatment of plasma cell tumors. Pctr2 joins Pctr1 in possessing alleles that modify susceptibility to plasmacytomagenesis by encoding differences in efficiency of function (efficiency alleles), rather than all-or-none, gain-of-function, or loss-of-function alleles. By analogy, human cancer may also result from the combined effects of several inefficient alleles.
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PMID:Frap, FKBP12 rapamycin-associated protein, is a candidate gene for the plasmacytoma resistance locus Pctr2 and can act as a tumor suppressor gene. 1463 9

The cutaneous human papillomavirus (HPV) 8 is clearly involved in skin cancer development in epidermodysplasia verruciformis patients and its early genes E2, E6, and E7 have been implicated in cell transformation in vitro. To examine the functions of these genes in vivo we integrated the complete early region of HPV8 into the genome of DBA/Bl6 mice. To target their expression to the basal layer of the squamous epithelia the transgenes were put under the control of the keratin-14 promoter. Transgenic mice were back-crossed for up to six generations into both FVB/N and Bl6 mouse strains. Whereas none of the HPV8 transgene-negative littermates developed lesions in the skin or any other organ, 91% of HPV8-transgenic mice developed single or multifocal benign tumors, characterized by papillomatosis, acanthosis, hyperkeratosis, and varying degrees of epidermal dysplasia. Squamous cell carcinomas developed in 6% of the transgenic FVB/N mice. Real-time reverse transcription-PCR showed highest expression levels for HPV8-E2, followed by E7 and E6. There was no consistent difference in relative viral RNA levels between healthy or dysplastic skin and malignant skin tumors. Whereas UV-induced mutations in the tumor suppressor gene p53 are frequently detected in human skin carcinomas, mutations in p53 were not observed either in the benign or malignant mouse tumors. Nonmelanoma skin cancer developed in HPV8-transgenic mice without any treatment with physical or chemical carcinogens. This is the first experimental proof of the carcinogenic potential of an epidermodysplasia verruciformis-associated HPV-type in vivo.
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PMID:Development of skin tumors in mice transgenic for early genes of human papillomavirus type 8. 1573 26

The response of mammalian cells to ionizing radiation can be directly influenced by genetics, and mouse strains can be identified that differ in their cellular radiosensitivity. The C57BL/6 radiation resistant and DBA/2 radiation susceptible mouse strains were utilized to aid the elucidation of the mechanisms involved in the early response to ionizing radiation. Investigation of the p53 pathway revealed differences in the expression and activity of p53 and its downstream targets between these mouse strains. The radiation resistant C57BL/6 strain showed an early p53 response and preferentially upregulated pro-apoptotic Bax, whereas the radiation sensitive DBA/2 strain exhibited a later, more prolonged p53 response and a greater expression of the cyclin dependent kinase inhibitor p21. These two mouse strains also showed significantly different levels of splenic radiation-induced apoptosis, the radiation resistant C57BL/6 scoring twofold more apoptotic cells than its radiation sensitive counterpart. These data provided a quantitative endpoint for an apoptosis genetic linkage analysis. The preliminary results of the linkage analysis indicated that three distinct loci may be involved in driving the different apoptosis phenotypes exhibited by the mouse strains. Moreover, we ascertained whether the mechanisms involved in the response to ionizing radiation may work in a tissue-specific fashion. In the linkage analysis, comparison of apoptosis scores in the colon and small intestine with data from the spleen showed little correlation suggesting that levels of apoptosis are tissue-specific. Tissue-specificity in the colon and small intestine was further illustrated by work with a 2D gel electrophoresis system. This revealed different patterns of p53 phosphorylation between the intestinal tissues both before and after exposure to ionizing radiation. The data discussed here will aid our understanding of the genes and mechanisms involved in radiation responses.
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PMID:The genetic basis of tissue responses to ionizing radiation. 1770 22

Mutations in genes encoding ribosomal proteins cause the Minute phenotype in Drosophila and mice, and Diamond-Blackfan syndrome in humans. Here we report two mouse dark skin (Dsk) loci caused by mutations in Rps19 (ribosomal protein S19) and Rps20 (ribosomal protein S20). We identify a common pathophysiologic program in which p53 stabilization stimulates Kit ligand expression, and, consequently, epidermal melanocytosis via a paracrine mechanism. Accumulation of p53 also causes reduced body size and erythrocyte count. These results provide a mechanistic explanation for the diverse collection of phenotypes that accompany reduced dosage of genes encoding ribosomal proteins, and have implications for understanding normal human variation and human disease.
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PMID:Ribosomal mutations cause p53-mediated dark skin and pleiotropic effects. 1866 27

Pro-apoptotic Bax is essential for RGC (retinal ganglion cell) death. Gene dosage experiments in mice, yielding a single wild-type Bax allele, indicated that genetic background was able to influence the cell death phenotype. DBA/2J(Bax+/-) mice exhibited complete resistance to nerve damage after 2 weeks (similar to Bax(-/-) mice), but 129B6(Bax+/-) mice exhibited significant cell loss (similar to wild-type mice). The different cell death phenotype was associated with the level of Bax expression, where 129B6 neurons had twice the level of endogenous Bax mRNA and protein as DBA/2J neurons. Sequence analysis of the Bax promoters between these strains revealed a single nucleotide polymorphism (T(129B6) to C(DBA/2J)) at position -515. A 1.5- to 2.5-fold increase in transcriptional activity was observed from the 129B6 promoter in transient transfection assays in a variety of cell types, including RGC5 cells derived from rat RGCs. Since this polymorphism occurred in a p53 half-site, we investigated the requirement of p53 for the differential transcriptional activity. Differential transcriptional activity from either 129B6 or DBA/2J Bax promoters were unaffected in p53(-/-) cells, and addition of exogenous p53 had no further effect on this difference, thus a role for p53 was excluded. Competitive electrophoretic mobility-shift assays identified two DNA-protein complexes that interacted with the polymorphic region. Those forming Complex 1 bound with higher affinity to the 129B6 polymorphic site, suggesting that these proteins probably comprised a transcriptional activator complex. These studies implicated quantitative expression of the Bax gene as playing a possible role in neuronal susceptibility to damaging stimuli.
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PMID:A single nucleotide polymorphism in the Bax gene promoter affects transcription and influences retinal ganglion cell death. 2036 Sep 47

Diamond-Blackfan anaemia (DBA) is a cancer-prone genetic disorder characterized by pure red-cell aplasia and associated physical deformities. The ribosomal protein S19 gene (RPS19) is the most frequently mutated gene in DBA (~25%). TP53-mediated cell cycle arrest and/or apoptosis in erythroid cells have been suggested to be major factors for DBA development, but it is not clear why mutations in the ubiquitously expressed RPS19 gene specifically affect erythropoiesis. Previously, we showed that RPS19 deficiency in zebrafish recapitulates the erythropoietic and developmental phenotypes of DBA, including defective erythropoiesis with severe anaemia. In this study, we analysed the simultaneous loss-of-function of RPS19 and Tp53 in zebrafish to investigate the role of Tp53 in the erythroid and morphological defects associated with RPS19 deficiency. Co-inhibition of Tp53 activity rescued the morphological abnormalities, but did not alleviate erythroid aplasia in RPS19-deficient zebrafish. In addition, knockdown of two other RP genes, rps3a and rpl36a, which result in severe morphological abnormalities but only mild erythroid defects, also elicited an activated Tp53 response. These results suggest that a Tp53-independent but RPS19-dependent pathway could be responsible for defective erythropoiesis in RPS19-deficient zebrafish.
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PMID:Erythropoiesis failure due to RPS19 deficiency is independent of an activated Tp53 response in a zebrafish model of Diamond-Blackfan anaemia. 2122 53

Diamond-Blackfan anemia (DBA) is a congenital erythroid hypoplasia caused by a functional haploinsufficiency of genes encoding for ribosomal proteins. Among these genes, ribosomal protein S19 (RPS19) is mutated most frequently. Generation of animal models for diseases like DBA is challenging because the phenotype is highly dependent on the level of RPS19 down-regulation. We report the generation of mouse models for RPS19-deficient DBA using transgenic RNA interference that allows an inducible and graded down-regulation of Rps19. Rps19-deficient mice develop a macrocytic anemia together with leukocytopenia and variable platelet count that with time leads to the exhaustion of hematopoietic stem cells and bone marrow failure. Both RPS19 gene transfer and the loss of p53 rescue the DBA phenotype implying the potential of the models for testing novel therapies. This study demonstrates the feasibility of transgenic RNA interference to generate mouse models for human diseases caused by haploinsufficient expression of a gene.
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PMID:Mice with ribosomal protein S19 deficiency develop bone marrow failure and symptoms like patients with Diamond-Blackfan anemia. 2198 89

Colorectal cancer (CRC) has become one of the most common fatal cancers. CRC tumorigenesis is a complex process involving multiple genetic changes to several sequential mutations or molecular alterations. P53 is one of the most significant genes; its mutations account for more than half of all CRC. Therefore, understanding the cellular genes that are directly or indirectly related to p53 is particularly crucial for investigating CRC tumorigenesis. In this study, a p53-related ribosomal protein, ribosomal protein S19 (RPS19), obtained from the feces of CRC patients is evaluated by using specifically quantitative real-time PCR and knocked down in the colonic cell line by gene silencing. This study found that CRC patients with higher expressions of RPS19 in their feces had a better prognosis and consistent expressions of RPS19 and BAX in their colonic cells. In conclusion, the potential mechanism of RPS19 in CRC possibly involves cellular apoptosis through the BAX/p53 pathway, and the levels of fecal RPS19 may function as a prognostic predictor for CRC patients.
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PMID:Lowly expressed ribosomal protein s19 in the feces of patients with colorectal cancer. 2227 77


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