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 aim of this work was to study the role of the tumor suppressor p53 and of poly(ADP-ribose) transferase (pADPRT) in the control of hepatocyte apoptosis in two different in vivo models, i.e., during the process of tumor initiation by the genotoxin and cytotoxin N-nitrosomorpholine (NNM) and after withdrawal of the hepatomitogen cyproterone acetate (CPA). Treatment with NNM induces apoptosis followed by necrosis and regenerative DNA synthesis. At the first wave of apoptosis 12 h after NNM application, no p53 expression could be detected by immunohistochemical analysis and immunoblotting. However, 24 h after treatment, numerous p53-positive hepatocyte nuclei were detected, whereas hepatocytes in early and later stages of apoptosis were always negative. Simultaneously with the increased p53 levels, p21 protein was induced. This was accompanied by a block in replicative DNA synthesis, as detected by proliferating-cell nuclear antigen immunostaining. Concomitantly with the increase in apoptosis, dramatic degradation of the nuclear enzyme pADPRT was observed, as evidenced by immunoblotting and activity blotting. The decrease in pADPRT enzymatic activity observed 12 h after treatment coincided with the greatest extent of pADPRT cleavage. One prominent cleavage product was 64 kDa, suggesting that granzyme B was involved in pADPRT degradation. In the second in vivo model we used, i.e., withdrawal of treatment with the hepatomitogen CPA, apoptosis of excessive hepatocytes but no necrosis occurs. Again, no induction of p53 expression could be detected in the liver even at the maximum level of apoptosis, whereas a strong correlation between induction of apoptosis and cleavage of pADPRT to a 64-kDa fragment was observed. These results from whole-animal experiments strongly suggest that the induction of apoptosis in rat liver after genotoxic and cytotoxic damage and during regression of hyperplasia is driven by a p53-independent pathway but is accompanied by cleavage of pADPRT.
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PMID:Cleavage of poly(ADP-ribose) transferase during p53-independent apoptosis in rat liver after treatment with N-nitrosomorpholine and cyproterone acetate. 1032 63

The incidence of melanoma, the most aggressive tumor of the skin, is increasing worldwide. The genetic mechanisms responsible for the initiation and progression of melanoma are poorly understood. Mutations of p16 (CDKN2), p53, ras, neurofibromatosis type I gene (NF-1), bcl2 and the retinoblastoma gene have been described, but none are common. Suggesting heterogeneous mechanisms of carcinogenesis. Both familial inheritance of potential tumor suppressor genes, e.g. p16, and differences in DNA-repair capacity contribute to the individual risk for melanoma. The most important carcinogen for melanoma seems to be u.v. exposition whose mutagenic effects can be demonstrated by molecular analysis of detected point mutations in relevant genes. The u.v.-induced DNA damage generates mutations which are capable of activating proto-oncogenes or inactivating tumor suppressor genes, demonstrating the molecular link between u.v. exposition, DNA damage, mutations and tumor initiation and/or progression. A stage-dependent model of melanoma carcinogenesis analogous to colorectal cancer remains to be established, despite the existence of morphologically and histopathologically well defined melanoma precursor lesions in the skin.
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PMID:[Pathogenesis of malignant melanoma. Molecular biology aspect]. 1042 7

We observed previously that wild-type p53 rendered neonatal mouse astrocytes resistant to 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) in a gene dose-dependent fashion. This effect of p53 appeared to be unrelated to its cell cycle regulation or apoptotic functions. Because in many cell types O(6)-methylguanine-DNA methyltransferase (MGMT)-mediated DNA repair is an important mechanism of resistance to nitrosoureas, we measured MGMT activity in wild-type, heterozygous and p53 knockout neonatal mouse astrocytes. Wild-type p53 astrocytes had significantly greater MGMT activity than either heterozygous or p53 knockout astrocytes: MGMT activity was approximately 5-fold greater in wild-type p53 astrocytes than in p53 knockout cells. However, despite successful depletion of MGMT activity in wild-type astrocytes by O(6)-benzylguanine (BG), resistance to BCNU persisted unchanged. Moreover, we excluded the possibility that continued resistance to BCNU at the concentrations used could be explained by a compensatory induction of MGMT triggered by exposure to either BCNU or BG. Although these studies support a role for p53 regulation of MGMT in neonatal mouse astrocytes, BCNU resistance in wild-type cells appears to be mediated by a non-MGMT mechanism. Nevertheless, regulation of DNA repair by MGMT may be another mechanism by which alterations of the p53 gene promote tumor initiation or progression.
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PMID:O(6)-methylguanine-DNA methyltransferase activity, p53 gene status and BCNU resistance in mouse astrocytes. 1059 Feb 34

The p53 tumor suppressor protein participates in multiple cellular processes including cell cycle checkpoints and programmed cell death. In cell lines, loss of p53 function is associated with increased genetic instability including aneuploidy, gene amplification, and point mutation. Although similar genetic instability often accompanies the progression of malignancy in tumors, its role in tumor initiation in normal cells is not clear. To study whether or not loss of p53 leads to genetic instability in normal cells in vivo, we have examined mechanisms of loss of heterozygosity (LOH) at the Aprt (adenine phosphoribsyltransferase) and flanking loci in normal fibroblasts and T lymphocytes of p53-deficient mice. Somatic cell variants that arose in vivo as a consequence of genetic or epigenetic alterations abolishing Aprt function were selected and expanded in vitro by virtue of their resistance to 2,6-diaminopurine (DAP). We observed that p53 null mice produced about three times as many DAP-resistant fibroblast colonies than wild-type mice, but the frequency of DAP-resistant T lymphocyte colonies was not significantly changed. Mitotic recombination, but not point mutation, partly accounted for the increase in the frequency of DAP-resistant fibroblasts. Most significantly, chromosome loss/duplication and interstitial deletion, which were extremely rare events in the wild-type mice, represented a significant proportion of LOH events in both fibroblasts and T lymphocytes of p53 null mice. Also, increased interstitial deletion was observed in fibroblasts of p53 heterozygous mice. These data suggest that increased genetic variation, including chromosome instability, starts at the initiation stage of tumorigenesis when functional p53 is absent or reduced.
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PMID:Chromosome instability contributes to loss of heterozygosity in mice lacking p53. 1086 Oct 8

Activating mutations of RAS are thought to be early events in the evolution of thyroid follicular neoplasms. We used a doxycycline-inducible expression system to explore the acute effects of H-RAS12 on genomic stability in thyroid PCCL3 cells. At 2-3 days (first or second cell cycle) there was a significant increase in the frequency of micronucleation. Treatment of cells with YVAD-CHO inhibited RAS-induced apoptosis, but had no effect on micronucleation. The effects of H-RAS(V12) were mediated by activation of MAPK, as treatment with PD98059 at concentrations verified to selectively inhibit MEK1 reduced the frequency of prevalence of cells with micronuclei. In addition, doxycycline-inducible expression of a constitutively active MEK1, but not of a mutant RAC1, mimicked the effects of H-RAS(V12). The effects of H-RAS(V12) on genome destabilization were apparent even though the sequence of p53 in PCCL3 cells was confirmed to be wild-type. Acute activation of H-RAS(V12) evoked a proportional increase in both CREST negative and CREST positive micronuclei, indicating that both clastogenic and aneugenic effects were involved. H-RAS(V12) and activated MEK1 also induced centrosome amplification, and chromosome misalignment. Evidence that acute expression of constitutively activated RAS destabilizes the genome of PCCL3 cells is consistent with a mode of tumor initiation in which this oncogene promotes phenotypic progression by predisposing to large scale genomic abnormalities.
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PMID:The RAS oncogene induces genomic instability in thyroid PCCL3 cells via the MAPK pathway. 1095 88

The tumor suppressor gene p53 is perhaps the most commonly mutated gene in human cancer, being mutated in a high percentage of colon, breast, skin, bladder, and many cancers of the aerodigestive tract. Individuals with Li-Fraumeni syndrome, who routinely have a germline mutation in the p53 tumor suppressor gene, are at high risk for lung cancer, confirming its intimate role in lung tumorigenesis in humans. In contrast, the majority of chemically induced or spontaneous cancers in rodents do not contain mutations in p53. Therefore, we examined a transgenic mouse that contains a dominant negative mutation (Arg135Val) in the p53 gene placed under the control of its own endogenous promoter. The resulting mice have 3 copies of the mutated transgene as well as 2 normal p53 alleles. In the chemical carcinogenesis studies, we employed mice containing the mutated p53 gene to examine for carcinogen susceptibility. We found that mice with the p53 mutation, on an A/J F1 background, were more susceptible to a number of potential lung carcinogens, including N-methyl-N-nitrosourea (MNU) and the known tobacco carcinogens 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and benzo(a)pyrene (BP). Mice with a mutant p53 developed larger tumors and roughly 3 times as many tumors, emphasizing the potential effects of a p53 mutation both on tumor initiation and progression. In addition, we examined 2 nonlung carcinogens, 1,2-dimethylhydrazine (DMH), a colon carcinogen, and N-butyl-N-(4-hydroxybutyl)-nitrosamine (OHBBN), a bladder carcinogen. Interestingly a germline p53 mutation increased the incidence of DMH-induced colon, lung, hepatic, and uterine tumors, while having limited effects on OHBBN-induced bladder tumors. Because of its heightened susceptibility we are examining the use of this model in smoke-induced tumorigenesis in A/J mice as well. Employing the lung adenomas induced by NNK, we found that mice with or without a p53 mutation were equally susceptible to the chemopreventive effects of dexamethasone plus myo-inisitol and green tea. These tumors, which arise in a highly reproducible manner in p53 transgenic mice following carcinogen treatment, have mutations in both p53 and the K-ras oncogene. Thus, this model appears useful for examining for potential chemotherapeutic agents. p53-mutated or wild-type mice were equally susceptible to the therapeutic effects of Taxol or Adriamycin. Interestingly, piroxicam was similarly effective in inhibiting colon tumor formation by DMH in mice with or without a mutation in the p53 tumor suppressor gene. In contrast, lung and uterine tumors developing in these mice were not susceptible to the chemopreventive effects of piroxicam. In summary, mice with mutations in the p53 tumor suppressor gene appear to be particularly applicable for basic mechanistic studies, for screening for potential carcinogens, and for screening for chemopreventive or chemotherapeutic agents.
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PMID:Use of p53 transgenic mice in the development of cancer models for multiple purposes. 1119 57

The molecular pathways and the timing of genetic events during human colorectal carcinogenesis are still not fully understood. We have addressed the intratumor heterogeneity of the mutational status of the k-ras oncogene and of the p53 oncosuppressor gene during the adenoma-carcinoma sequence by investigating 26 human colorectal adenomas containing early cancer. An intratumor comparative analysis was obtained among the adenomatous and carcinomatous component pairs. Additionally, we have analyzed 17 adenomas having cancer in the near vicinity. The adenomatous components of the adenomas containing early cancer and the adenomas having cancer in the near vicinity had comparable frequencies for k-ras mutations (28 and 47%) but different for p53 mutations (52 and 7%, p-value = 0.01). Interestingly, the adenomatous and carcinomatous components of the adenomas containing early cancer were rarely heterogeneous for the k-ras mutational status (only in 13% of the cases) but were characterized by heterogeneity of the p53 status in 59% of the cases (p-value < 0.01). In addition, the mutations of p53 for the adenomatous components of the adenomas containing early cancer were statistically significantly associated with severe dysplasia (p-value = 0.01). Intratumor homogeneity of k-ras status during the human colorectal adenoma-carcinoma sequence suggests that the role of k-ras is more related to tumor initiation than to tumor progression. On the contrary, intratumor heterogeneity of p53 mutations indicates that the type of the p53 mutations may also be relevant for selection and expansion of new subclones leading to tumor progression.
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PMID:Intratumor heterogeneity of k-ras and p53 mutations among human colorectal adenomas containing early cancer. 1131 Jun 41

Inactivation of wild-type p53 tumor suppressor function is the primary mechanism of tumor initiation in Li-Fraumeni syndrome (LFS) individuals with germline p53 mutations. Tumors derived from LFS patients frequently retain the normal p53 allele, suggesting that alternative mechanisms in addition to gene deletion must be involved in inactivating wild-type p53 protein. DNA tumor viruses, such as SV40, target p53 for inactivation through the action of viral oncoproteins. We studied the probands from two unrelated LFS families, each of whom presented with multiple malignant neoplasms. Patient 1 developed an embryonal rhabdomyosarcoma (RMS) and a choroid plexus carcinoma (CPC), while patient 2 developed a CPC and subsequently presented with both an osteosarcoma (OS) and renal cell carcinoma (RCC). We utilized DNA sequence analysis and immunohistochemistry to determine p53 gene status in the germline and tumors, as well as evidence for SV40 T-antigen oncoprotein expression. Each patient harbored a heterozygous germline p53 mutation at codons 175 and 273, respectively. In patient 1, the normal p53 gene was lost while the mutant p53 allele was reduced to homozygosity in the RMS. Both normal and mutant genes were maintained in the CPC. In patient 2, normal and mutant p53 alleles were retained in both the CPC and RCC. Both specific PCR and immunostaining detected SV40 T-antigen in both CPCs and the RCC. In addition to chromosomal alterations, epigenetic mechanisms may disrupt p53 function during tumorigenesis. In two LFS patients, we found SV40 DNA sequences and viral T-antigen expression that could account for inactivation of the normal p53 protein. Inactivation of p53 or other tumor suppressors by viral proteins may contribute to tumor formation in specific tissues of genetically susceptible individuals.
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PMID:Tissue-specific expression of SV40 in tumors associated with the Li-Fraumeni syndrome. 1149 39

Death associated protein kinase (DAP-kinase) is a pro-apoptotic calcium/calmodulin-regulated serine/threonine kinase with a multidomain structure that participates in a wide array of apoptotic systems initiated by IFN-gamma, TNF-alpha, activated Fas, and detachment from extracellular matrix. At various stages during tumor development, cells are subjected to apoptosis inducing stimuli and genetic mutations causing inhibition of apoptosis confer a selective advantage to cells. Thus, apoptosis and its regulation play an important role in tumor initiation, progression and metastasis. It has been demonstrated that the tumor-suppressive properties of DAP-kinase operate at two different apoptotic checkpoints in the course of tumor development; first, during the early oncogene-activated apoptotic checkpoint mediated by p19ARF-p53 pathway and second, during the late stages of metastasizing cells entering the circulation after detachment from extracellular matrix. Promoter hypermethylation of DAP-kinase has been observed in a high variety of primary tumors including head and neck tumors, and non-small cell lung cancers, where an association with poor prognosis was also noted. Notably, high frequencies of DAP-kinase methylation have been found in B cell lymphomas and myeloma, where loss of control of c-Myc induced hyperproliferation from inactivated DAP-kinase may possibly play an important role in the pathogenesis of these B cell neoplasms.
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PMID:Death associated protein kinase: from regulation of apoptosis to tumor suppressive functions and B cell malignancies. 1199 70

Prostate cancer prevention by key elements present in human nutrients derived from plants and fruits has been confirmed in various cell cultures and tumor models. Resveratrol (RE), a phytoalexin, induces remarkable inhibitory effects in prostate carcinogenesis via diverse cellular mechanisms associated with tumor initiation, promotion and progression. Earlier studies have shown that RE alters the expression of genes involved in cell cycle regulation and apoptosis, including cyclins, cdks, p53 and cdk inhibitors. However, most of the p53-controlled effects related to the role of RE in transcription either by activation or repression of a sizable number of primary and secondary target genes have not been investigated. Our study examined whether RE activates a cascade of p53-directed genes that are involved in apoptosis mechanism(s) or whether it modifies the androgen receptor and its co-activators directly or indirectly and induces cell growth inhibition. We demonstrate by DNA microarray, RT-PCR, Western blot and immunofluorescence analyses that treatment of androgen-sensitive prostate cancer cells (LNCaP) with 10(-5) M RE for 48 hr downregulates prostate-specific antigen (PSA), AR co-activator ARA 24 and NF-kB p65. Altered expression of these genes is associated with an activation of p53-responsive genes such as p53, PIG 7, p21(Waf1-Cip1), p300/CBP and Apaf-1. The effect of RE on p300/CBP plays a central role in its cancer preventive mechanisms in LNCaP cells. Our results implicate activation of more than one set of functionally related molecular targets. At this point we have identified some of the key molecular targets associated with AR and p53 target genes. These findings point to the need for further extensive studies on AR co-activators, such as p300, its central role in post-translational modifications such as acetylation of p53 and/or AR by RE in a time- and dose-dependent manner at different stages of prostate cancer that will fully elucidate the role of RE as a chemopreventive agent for prostate cancer in humans.
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PMID:Differential expression of genes induced by resveratrol in LNCaP cells: P53-mediated molecular targets. 2727 1


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