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)

Experimental models relating to human glioblastoma multiformes (hGBMs) involve the intracranial or intracerebral injection of human GBM cells into nude mice or rats. The aim of the present study was to compare a number of biological characteristics of hGBMs as opposed to experimental GBMs obtained by grafting either human U87 or U373 glioblastoma cells into the brains of nude mice. Biological assessments involve four distinct sets of parameters, i.e. i) the determination of the nuclear DNA content, ii) the determination of proliferative activity, iii) the assessment of p53 nuclear phosphoprotein immunohistochemical reactivity, and iv) the assessment of GFAP, VIM, LEU-7, S-100 and CAT D protein immunohistochemical reactivity. While most of the human glioblastoma multiformes (hGBMs) under study were immunohistochemically reactive to GFAP, S-100, LEU-7 and VIM as indeed were the experimental U373 GBMs, the U87 ones were reactive to VIM only. Furthermore, the U87 GBMs appeared to be more aggressive than the U373 ones since the former were associated with a shorter tumor-bearing mouse survival time than the latter. Such aggressiveness was further associated with a proliferative activity and a cathepsin D immunoreactivity, both of which were markedly higher in the U87 GBMs than in the U373 GBMs. These two experimental GBM models also exhibited tumors which were predominantly diploid. The present study shows that it is possible to set up experimentally in vivo models which strongly mimic human glioblastoma multiformes. Such models consist of grafting human glioblastoma cell lines, namely U87 and U373, into the brains of nude mice. However, while it is true that experimental GBMs closely resemble the hGBMs with respect to some biological characteristics, they also differ in many other significant biological characteristics.
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PMID:The characterization of nuclear-DNA content, the proliferative activity and the immunohistochemical expression of gfap, vim, leu-7, s-100, p53 and cathepsin-d in human glioblastoma multiformes (hgbms) versus human gbm cell-lines grafted into the brains of nude-mice. 2155 62

Genomic instability is thought to be critical for the development of cancer. Among its causes microsatellite instability (MIN) and chromosomal instability (CIN) have attracted the most attention. Cell cycle checkpoints and DNA repair mechanisms are the first line of defense against DNA damage. Among the most dangerous DNA lesions are double-strand breaks. The response to DNA double strand breaks is regulated mainly by the serine/threonine kinases ATM and Chk2 and their downstream target the tumor suppressor p53, which in turn stimulates the expression of growth-inhibitory genes like p21 or pro-apoptotic genes like Bax. The balance between these gene products determines the fate of a cell. EAPP is a nuclear phosphoprotein that is frequently upregulated in human tumors. We have recently shown that EAPP levels are critical for cellular homeostasis. DNA damage elevates EAPP levels and its overexpression results in G1 arrest and impairs apoptosis in a p21-dependent manner. EAPP binds to the p21 promoter, stimulates its activity and seems to be essential for transcription initiation. In the present work we show that EAPP also regulates the phosphorylation status and thus the activity of Chk2. EAPP binding seems to trigger the dephosphorylation of P-Chk2 resulting in its inactivation. A newly described function of Chk2 in mitosis that secures genomic integrity might also be affected by EAPP overexpression. This might explain the abundance of EAPP in aneuploid tumor cells.
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PMID:EAPP modulates the activity of p21 and Chk2. 2157 56

Mutations in the nuclear phosphoprotein p53 are the most frequent genetic alterations in human solid tumors detected so far. These mutations are clustered in highly conserved domains spanning from exon 4 to 9 of the gene. A very precise method of detecting p53 mutations is to sequence these domains. However, 2 to 3 overlapping PCR-amplifications were needed to span the whole mutation-prone region. We used a very rapid non radioactive solid-phase DNA sequencing method starting from mRNA to sequence the p53 domains in both directions with T7 DNA-polymerase allowing detection of the heterozygous state, where one allele shows the wild-type sequence, the other a mutated one. First we sequenced four colon carcinoma cell lines with known p53 mutations and one T-cell-leukemia cell line with a heterozygous situation to validate our method. Using this method we sequenced the p53 gene (exons four to nine) from 16 primary colon carcinomas. Seven of these 16 (44%) carcinomas showed mutations in the p53 gene resulting in amino acid exchanges. One showed a silent mutation, another one showed two point mutations in the highly conserved domain of the p53 gene. These colorectal carcinomas have been examined for overexpression of the p53 protein using a panel of monoclonal antibodies directed against p53 (PAb1801, PAb240, PAb421, PAb1620) by immunohistochemical analysis and immunoblotting. Furthermore, four colorectal cancer cell lines were examined by indirect immunofluorescence technique with the same mAb PAb1801 as used in histological staining. Analysis of 6 out of 15 (40%) tumor specimens revealed markedly positive p53 nuclear staining patterns using monoclonal antibody PAb1801. These data suggest that there is quite a good correlation between point mutation of the p53 gene and nuclear staining with monoclonal antibody PAb1801 detecting overexpressed p53 protein. Moreover, there is no convincing evidence that wild-type protein can be detected using the monoclonal antibodies PAb 1801 and PAb 1620.
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PMID:Mutation and expression of the p53 tumor suppressor gene in tumor samples and cancer cell-lines - comparison of nonisotopic direct DNA-sequencing, immunoblotting and immunohistochemistry. 2157 61

The nuclear phosphoprotein p53, named according to its apparent molecular weight on SDS-polyacrylamide gels is expressed, albeit at low levels, in a variety of cell types. In normal cells, it seems to be required for cell proliferation whereas in transformed cells it is frequently a target for mutations. Wild-type p53 has a growth-suppressor function which is completely abolished in mutant p53. However, there is ample evidence that mutant p53 has not only lost the suppressor activity but contributes as a dominant oncogene to tumorigenesis. In line with these observations wild-type p53 has a growth inhibitory function even when introduced in rapidly proliferating tumor cells whereas mutant p53 has a growth promoting function. Wild-type p53 and mutant p53 exhibit different DNA binding activities which may be implicated in transcriptional regulation and in DNA replication. Furthermore, both wild-type and mutant p53 play a role in controlling the transition of cells through at least two different restriction points of the cell cycle. Besides these functions in growth control p53 also plays an active role during embryonic development. Expression of p53 is high in cells predetermined to differentiate and decreases upon differentiation. Since embryonic cells express wild-type p53, a progressive role during differentiation has to be attributed to wild-type p53. Thus, this review will try to highlight some of the significant advances in the most rapidly evolving field of the functional implications of p53 in cell biology and tumorigenesis.
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PMID:Functional implications of the growth-suppressor oncoprotein p53. 2158 7

The TP53 gene, first described in 1979, was identified as a tumor suppressor gene in 1989, when it became clear that its product, the p53 nuclear phosphoprotein, was frequently inactivated in many different forms of cancers. Nicknamed "guardian of the genome", TP53 occupies a central node in stress response networks. The p53 protein has a key role as transcription factor in limiting oncogenesis through several growth suppressive functions, such as initiating apoptosis, senescence, or cell cycle arrest. The p53 protein is directly inactivated in about 50% of all tumors as a result of somatic gene mutations or deletions, and over 80% of tumors demonstrate dysfunctional p53 signaling. Beyond the undeniable importance of p53 as a tumor suppressor, an increasing number of new functions for p53 have been reported, including its ability to regulate energy metabolism, to control autophagy, and to participate in various aspects of differentiation and development. Recently, studies on genetic variations in TP53 among different populations have led to the notion that the p53 protein might play an important role in regulating fertility. This review summarizes current knowledge on the basic functions of different genes of the TP53 family and TP53 pathway with respect to fertility. We also provide original analyses based on genomic and genotype databases, providing further insights into the possible roles of the TP53 pathway in human reproduction.
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PMID:The TP53 fertility network. 2341 5

Intracellular pathogen resistance 1 (Ipr1) has been found to be a mediator to integrate cyclic GMP-AMP synthase (cGAS)-interferon regulatory factor 3 (IRF3), activated by intracellular pathogens, with the p53 pathway. Previous studies have shown the process of Ipr1 induction by various immune reactions, including intracellular bacterial and viral infections. The present study demonstrated that Ipr1 is regulated by the cGAS-IRF3 pathway during pathogenic infection. IRF3 was found to regulate Ipr1 expression by directly binding the interferon-stimulated response element motif of the Ipr1 promoter. Knockdown of Ipr1 decreased the expression of immunity-related GTPase family M member 1 (Irgm1), which plays critical roles in autophagy initiation. Irgm1 promoter characterization revealed a p53 motif in front of the transcription start site. P53 was found to participate in regulation of Irgm1 expression and IPR1-related effects on P53 stability by affecting interactions between ribosomal protein L11 (RPL11) and transformed mouse 3T3 cell double minute 2 (MDM2). Our results indicate that Ipr1 integrates cGAS-IRF3 with p53-modulated Irgm1 expression.
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PMID:Ipr1 Regulation by Cyclic GMP-AMP Synthase/Interferon Regulatory Factor 3 and Modulation of Irgm1 Expression via p53. 3198 6


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