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 incidence of primary brain tumors has increased dramatically among elderly North Americans during the past two decades. Numerous chromosomal abnormalities have been associated with these tumors; various subsets of these abnormalities are specific to certain types of brain tumors. Astrocytic gliomas may exhibit losses of genetic information from chromosomes 9p, 10q, 11p, 13q, 17p, or 22. Mutations of the p53 gene are found mostly in the malignant astrocytic forms and have been linked to malignant tumor transformation and progression. Functional and structural abnormalities of the neurofibromatosis 1 (NF1) gene and overexpression of the epidermal growth factor receptor have been associated with expression of the malignant glioma phenotype. Other less clearly defined abnormalities in astrocytomas include mutations of the retinoblastoma (RB) gene and overexpression of platelet-derived growth factor; transforming growth factor-alpha and -beta; the c-erb B-1, c-myc, ras, c-fos, and ros oncogenes; and insulin-like growth factor I and II. In other glioma tumors, p53 mutations are either infrequent, as in oligodendrogliomas, or absent, as in ependymomas. Occasionally, medulloblastomas exhibit p53 mutations and loss of genetic information from chromosomes 6q and 16q or expression of the c-erb B-2 oncogene. Loss of heterozygosity in chromosome 22 is the most frequent event in meningiomas, suggesting the presence of a tumor-suppressor gene in this chromosome.
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PMID:Epidemiology, cytogenetics, and molecular biology of brain tumors. 849 8

The antioxidant alpha-tocopherol and the weaker antioxidant and prooxidant chemopreventative, beta-carotene have been shown to inhibit tumor cell growth in vivo and in vitro. In some epidemiologic studies their serum levels were demonstrated to be inversely related to the incidence of malignant tumor. We hypothesized two basic pathways triggered by antioxidants and prooxidants, which resulted in the control of tumor cell growth. These included changes in phosphorylation and ultimately transcription. Specifically, the prooxidant beta-carotene treatment produced an oxidative stress resulting in the selective induction of heat shock proteins (hsps). These proteins and other proteins that were possibly oxidized were associated with the increased expression of cyclins (A and D) and increased cdc2 kinase expression. An increase in expression of phosphoproteins, such as p53 (tumor suppressor form) was also discerned. The level of expression for the transcription factor c-fos was reduced. Growth factors that contribute to tumor cell growth were also reduced. Increased DNA fragmentation, depression of proliferation and intracellular calcium levels, the accumulation of tumor cells in G0-->G1, and morphologic changes, were consistent with programmed cell death. Antioxidants such as alpha-tocopherol bound to membrane-associated proteins could inhibit the development of peroxidation products (hydroxyl radicals (.OH)), which attack proteins and modify their function and promote their degradation. Some kinases such as, cdc2 may be increased in activity, which would explain the observed increased expression of tumor suppressor p53, the accumulation of the tumor cells in G1 of the cell cycle and the inhibition of tumor cell proliferation. A reduction in oxidant radicals could also reduce transcription factor products, such as c-myb. Indirectly this result may occur through changes in nuclear translocation (signaling) NF-AT or the Rel-related family of transcription factors, including NF-kB (p50 or p65) or inhibition of immunophilin-calmodulin activity. Although the data remains fragmentary there are common points for control for tumor cell growth resulting from the effects of alpha-tocopherol or beta-carotene treatment. These changes involve phosphorylation and protein expression. Ultimately there is a reduction of important transcription factor protein products, a reduction in response to growth factors, and suppression of cell proliferation, resulting in increased control of the cell cycle.
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PMID:Molecular and biochemical reprogramming of oncogenesis through the activity of prooxidants and antioxidants. 851 52

2-Acetylaminofluorene (2-AAF) is a complete carcinogen in rat liver. To investigate the specific properties, that distinguish 2-AAF from incomplete carcinogens, rats were fed 0.02% AAF in the diet for 6, 12, 16 weeks and some indicators of genotoxic and chronic toxic effects were studied immunohistochemically. GST-P, a marker for single initiated cells and preneoplastic foci, was induced in response to 2-AAF exposure. The effects were slight after 6 weeks of feeding, after 12 weeks GST-P-positive preneoplastic foci were present. The proto-oncogenes c-fos and c-jun are induced by several tumor promoters. In the present study c-FOS protein levels were increased in all 2-AAF treated animals at early stages not only in preneoplastic foci. However, all GST-P-positive foci were also c-FOS-positive. Surprisingly c-JUN was not enhanced in GST-P positive foci. It was comparatively expressed in hepatocytes and bile duct cells in all animals. We did not observe any immunolabeling for p53, either in preneoplastic foci or in hepatocytes from treated animals. A significant increase of apoptoses was noted in the whole liver lobule but also gathered in groups in the periportal area. The results support our proposal that oxidative stress and energy impairment in the mitochondria of periportal hepatocytes trigger morphological alterations in the rat liver.
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PMID:Early initiating and promoting effects in 2-AAF-induced rat liver carcinogenesis: an immunohistochemical study. 852 4

In order to assess the specificity of biotinylated anti-c-erbB-3 antibody, screening was performed on a series of tumour cell lines and lymphocytes. Staining was found to be consistent, with good reproducibility. Twenty-nine consecutive breast cancer samples were obtained from women treated with tamoxifen and undergoing elective mastectomy. Twenty-eight invasive ductal carcinomas and 1 DCIS were stained for c-erbB-3 expression: 2 were grade I (Bloom and Richardson), 15 grade II, and 11 grade III tumours, 1 being unclassified; 16 were axillary node positive and 10 node negative; in 2 cases no nodes were sampled. Tumours examined by flow cytometry were stained with cytokeratin FITC antibody and the cytokeratin-positive population gated. Using Mann-Whitney analysis no association was seen between c-erbB-3 expression and Bloom and Richardson grade or axillary node status. In the tumour samples c-erbB-3 expression was found to show as association with EGF-R (P = 0.021 r2 = 0.16), PgR (P = 0.02, r2 = 0.16), c-myc (P < 0.0001, r2 = 0.5), c-jun (P = 0.001, r2 = 0.4) and c-fos (P = 0.001, r2 = 0.5) but not with c-erbB-2 (P = 0.2, r2 = 0.06), ER (P = 0.4, r2 = 0.02) or p53 1801 (P = 0.05, r2 = 0.2). Expression of c-erbB-3 may not be an independent marker of prognosis, but it is associated with other markers of poor prognosis and early cellular events linked with aberrant growth and differentiation.
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PMID:A flow cytometric study of c-erbB-3 expression in breast cancer. 853 73

This study investigates whether insulin (a differentiation factor for lens epithelial cells) acts as a survival factor. In the absence of insulin, 6-day embryonic chicken lens epithelial explants undergo apoptosis as shown by changes in cell morphology, DNA fragmentation, and loss of trypan blue exclusion. Insulin inhibits these changes and promotes survival of the cells. Aurintricarboxylic acid suppresses the apoptosis of lens explants. In contrast to 6-day embryonic explants, 19-day embryonic explants survive in the absence of insulin, presumably due to an endogenous survival factor. To explore the mechanism of the action of insulin as a survival factor for 6-day embryonic lens explants, we compared the pattern of cell cycle markers (c-fos, c-jun, c-myc, p53, histone H3, thymidine kinase, and cyclin B) in both apoptotic and differentiating lens explants. In the presence of insulin, the expression of c-fos and c-jun was down-regulated after an initial induction. Expression of these genes was also induced in the absence of insulin, but mRNA levels remained elevated as the cells underwent apoptosis. In contrast, expression of c-myc, p53, histone H3, thymidine kinase, and cyclin B showed only minor differences in differentiating and apoptotic cells. Since c-fos and c-jun have been shown to play a role in apoptosis in other cell types, the ability of insulin to regulate expression of these genes may be central to its ability to act as a survival factor for lens epithelial cells.
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PMID:Insulin regulates expression of c-fos and c-jun and suppresses apoptosis of lens epithelial cells. 854 23

Biopsies from 25 juvenile nasopharyngeal angiofibromas (JNAs) and respective normal inferior turbinates were examined and compared. The expression patterns of the messenger RNAs (mRNAs) for various growth factors possibly involved in the growth of mesenchymal cells, as well as angiogenesis and fibrosis, were also compared. These growth factors included insulin-like growth factor II (IGF-II), basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), transforming growth factors-beta1 (TGF-beta1) and platelet-derived growth factors (PDGF-A and PDGF-B). Quantification of mRNA coding for proto-oncogenes and suppressor genes related to proliferation (i.e., c-myc, c-fos, p53) was also undertaken. Tumor and turbinates expressed similar levels of bFGF, VEGF, TGF-beta1, c-myc, c-fos, and PDGF-A mRNAs. The presence of TGF-beta1 protein was confirmed by immunohistochemistry in several structures that characterize the lesions of JNA, which suggests that TGF-beta1 may play a role in the development of the fibrous component of this tumor. PDGF-B and p53 were overexpressed (i.e., twice the mean level found in turbinates) in 50% and 32% of JNAs, respectively but there was no statistical significance when compared with controls. Statistically significant increased expression of IGF-II mRNA was observed in JNA (P = .04). IGF-II mRNA levels were correlated to p53 (P = .05) and PDGF-B (P = .034), indicating a possible synergistic action of such factors in JNA. The results of this study suggest that IGF-II might be a potential growth regulator of nasopharyngeal angiofibromas.
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PMID:Expression of growth factors, proto-oncogenes, and p53 in nasopharyngeal angiofibromas. 858 52

The p53 tumour suppressor protein is a potent transcription factor which plays a central role in the defence of cells against DNA damage and the propagation of malignant clones. We have previously shown that phosphorylation of serine 386 in mouse p53 by the growth- associated protein kinase, casein kinase II (CKII), plays an important role in the ability of p53 to block the proliferation of drug-resistant colonies. In this paper we show that blocking phosphorylation of serine 386 through an alanine substitution, or placing a constitutive negative charge at this position in the form of aspartate, had no significant influence on p53-dependent transcriptional activation of a promoter containing 13 copies of a p53 consensus binding sequence, or of the p21WAF1 promoter which is a natural target for p53. In contrast, the alanine mutant showed a weak reduction in the ability of p53 to repress expression from the c-fos promoter, which is a target for p53-dependent repression in vivo. Strikingly, when the repression of the SV40 early promoter was examined, a reduction in the repression capacity of up to 5-fold was observed. Moreover, repression of the SV40 promoter could be partially restored by aspartic acid substitution at the phosphorylation site. These data indicate that phosphorylation at a specific C-terminal site can selectively regulate p53-dependent repression, but not transactivation.
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PMID:Phosphorylation of p53 at the casein kinase II site selectively regulates p53-dependent transcriptional repression but not transactivation. 860 47

Cancer-related mutations of the p53 tumor suppressor gene are clustered in the four so-called 'hot spots', codons 175, 248, 273 and 281/282. By using recombination PCR in vitro mutagenesis, we introduced point mutations into the codon 273 of wild-type (wt) p53 (pC53-SN3) from Arg to His (pC53-273H [273H]), Asp (273D), Pro (273P), Lys (273K), Leu (273L) or Thr (273T), and compared their biological and biochemical activities with wt p53 and cancer-derived 175H, 248W and 273H/309S. Among them, 273H/309S, 273H and 273D as well as wt p53 transactivated the chloramphenicol acetyltransferase (CAT) gene placed downstream of the p53 binding consensus, while none of the other mutants including 273L did. Transcriptions from human c-fos and rat PCNA promoters were suppressed by wt p53 and 273D, while they were enhanced variously by all other mutants in Saos-2 and/or NIH3T3 cells. On the other hand, growth of human squamous carcinoma cell lines measured by the plating efficiency of G418-resistant colonies was enhanced by transfection of 175H, 248W, 273H/309S and 273P, while suppressed by not only wt p53, 273D and 273H but also 273L. Thus, 273H/309S enhanced cell growth in spite of its p53-specific transactivation activity, while 273L suppressed cell growth in spite of its complete loss of the p53-specific transactivation. We concluded that the sequence-specific transactivation of p53 is not always correlated with its growth inhibitory activity.
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PMID:The 273rd codon mutants of p53 show growth modulation activities not correlated with p53-specific transactivation activity. 864 76

Chronic administration of estrogen to male Syrian hamsters for 7.0 to 9.0 months induces a high frequency of estrogen-dependent renal cancers. We have proposed a sequential multistage scheme involving tubular cell damage, regenerative cell proliferation, aneuploidy, chromosomal imbalance, genetic instability, gene alteration, and amplification as essential steps for estrogen carcinogenesis in this model. A systematic study was undertaken to assess the expression of nuclear proto-oncogenes, c-myc, c-fos, and c-jun, and suppressor genes, p53 and WT-1, by Northern blot analysis to further support this scheme. Hamster kidney RNA, taken at monthly intervals (1.0 to 6.0 months) from diethylstilbestrol (DES)-treated castrated male hamsters and corresponding age-matched untreated controls was used in these studies, as well as primary estrogen-induced renal tumor RNA, for reference. Although no significant changes in the expression of these proto-oncogenes were detected in the first 4 months of estrogen treatment relative to age-matched controls, 2.1-kb c-myc expression was elevated 2.8- and 4.1-fold at 5.0 and 6.0 months, respectively. Moreover, the expression of 2.2-kb c-fos transcript rose 4.6- and 4.8-fold; and 3.2- and 2.7-kb c-jun expression increased 2.8- and 5.1-fold at these same respective estrogen treatment time intervals. Tumor suppressor gene expression, p53 and WT-1, was also evaluated in similar estrogen-exposed hamsters. Although no significant changes were found in hamster kidney p53 expression in the first 5.0 months of DES treatment, it rose 1.8-fold at 6.0 months of estrogen treatment and more than 2.0-fold in the primary renal tumor. In contrast, no detectable changes in WT-1 expression were found during the first 6.0 months of DES treatment. However, a dramatic 7.0-fold increase in WT-1 expression was observed in the primary renal tumor. It is evident that two WT-1 transcripts reside in the hamster kidney; a lower molecular weight transcript was found in the normal adult kidney, and a higher molecular weight 3.2-kb transcript was observed in the renal tumor, similar to that seen in the newborn mouse kidney. In summary, the estrogen-induced inappropriate gene expression, including p53, reported herein, is consistent with the view that the elevations seen in gene expression contribute to proliferative advantages of certain proximal tubular interstitial cells necessary for estrogen-driven tumor formation in the hamster.
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PMID:Estrogen-induced proto-oncogene and suppressor gene expression in the hamster kidney: significance for estrogen carcinogenesis. 865 6

In this review, we present examples of the contribution of transgenic mice to our knowledge concerning the type of cells that are able to repopulate a damaged liver and information on the factors and mechanisms involved in postnatal liver growth and regeneration. The transgenic technology offers the opportunity to evaluate the physiological consequences of perturbating expression of a given gene in vivo. It has provided insights into the concerted action of extracellular (HGF/SF, TGF-alpha, EGF, TGF-beta) and intracellular factors (c-myc, c-fos, c-jun, p53, c-met, and others) in liver regeneration. Transgenic mice can also contribute to the dissection of the molecular mechanisms responsible for the regulated expression of these factors, both at the transcriptional and the posttranscriptional level. An illustration of such a strategy is given by the study of the sequences involved in the posttranscriptional regulation of the c-myc proto-oncogene. The recent improvement of gene targeting, in which endogenous genes are inactivated by homologous recombination, represents a further step toward the study of the function of a particular gene. Inactivation of most of the factors described in this review has been undertaken. However, further studies of their role in liver growth control are impeded by the fact that the corresponding knockout mice die prematurely. This problem could be overcome by the advent of new techniques, which will be briefly presented, aimed at turning genes on and off at will and in a tissue-specific manner.
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PMID:Liver regeneration 7. Prometheus' myth revisited: transgenic mice as a powerful tool to study liver regeneration. 866 58


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