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)

Exposure of primary cultures of cerebellar granule cells for 15 min to micromolar concentrations of glutamate results in cell death of both necrotic and apoptotic types. Among the intracellular events triggered by glutamate, we identified two transcriptional factors: the p50 member of the NF-kappaB family and the tumor suppressor phosphoprotein p53. Pretreatment of the cultures with aspirin, which inhibits NF-kappaB activation, or with specific p53 antisense oligonucleotide, which inhibits p53 transcription, resulted in a complete prevention of glutamate-induced p53 induction and apoptosis. These findings suggest the existence of a transcriptional program activated by glutamate receptor stimulation in which p50 and p53 play a relevant role. Then, we studied the expression of two p53 downstream genes that could participate in the glutamate-induced pro-apoptotic pathway: p21, which codes for an inhibitor of different cyclin dependent kinases, and MSH2, which codes for a protein involved in the recognition and repair of DNA mismatches. We found that primary cerebellar neurons expressed p21 and MSH2 at very low levels in basal conditions. However, very soon after a brief exposure of the cells to glutamate, the expression of both proteins was dramatically enhanced.On these bases, we propose NF-kappaB, p53, p21 and MSH2 as relevant contributors of the glutamate-induced pro-apoptotic pathway. Understanding this cascade of nuclear events may unravel specific targets for pharmacological intervention for those neurological diseases in which excitatory amino acid-induced apoptosis plays a relevant role.
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PMID:Contribution of NF-kappaB and p53 in the glutamate-induced apoptosis. 1081 29

Several studies have shown that the presence of genetic instability can be associated to carcinogenesis process. The detection of microsatellite instability (MI) that consists of an expansion and/or deletion of DNA within repeat sequences, may constitute a sensitive marker for the presence of gene mutations. A series of 18 basal cell carcinoma (BCC) consecutive patients was examined for the presence of alteration in 12 DNA microsatellite markers, in order to better understand the molecular significance of MI in the genesis and progression of BCC. Molecular alterations were detected in 6 out of 12 analyzed microsatellite loci. Five out of 18 BCC samples showed loss of heterozygosity at chromosome loci localized in the vicinity of the tumor suppressor genes, whereas six out of 18 BCC patients presented at least one altered microsatellite (instability). We demonstrated molecular genetic alterations at 2p16 locus, in the proximity of MSH2 <mismatch repair> gene and 17p21, in the proximity of the p53 gene. These data validate and confirm a role of MI in genesis and progression of BCC, by analysis of markers localized at specific chromosome region in proximity of oncogenes and tumor suppressor genes.
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PMID:Molecular detection of microsatellite instability in basal cell carcinoma. 1094 49

The hereditary breast (BC) and ovarian (OC) cancer syndrome (HBOC) includes genetic alterations of various susceptibility genes such as TP53, ATM, PTEN or MSH2, MLH1, PMS1, PMS2, MSH3 and MSH6, BRCA1 and BRCA2. Germline mutations of the cancer-susceptibility genes BRCA1 and BRCA2 seem to be the major aetiology of the HBOC. Genetic counselling and identification of high-risk families may be essential (1) to provide the best method for genetic testing by explaining the sensitivity and specificity of the methods, (2) to offer the opportunity to participate in specific early cancer detection programmes (breast (self) palpation, ultrasound, mammography and magnetic resonance tomography for breast cancer; vaginal exploration and ultrasound for ovarian cancer), (3) to inform them about prophylactic medication (oral contraceptive pill (OCP), chemoprevention (tamoxifen, raloxifen, aromatase inhibitors)) or surgery (bilateral prophylactic mastectomy or oophorectomy) and (4) to provide individualized psychological support. To fulfil these broad demands, an inter-disciplinary counselling approach (gynaecological oncology, human genetics, molecular biology, psychotherapy) in the setting of a cancer genetic clinic seems the most appropriate. There, participation in predictive genetic testing or the use of preventive or therapeutic options may be discussed extensively with the subjects. In particular, preventive options are emotionally disturbing for the subjects, and in cases of previous cancer. BC chemoprevention for high-risk women does not seem to be as effective as expected. However, OCP reduces the risk for OC. For prophylactic surgery, various points have to be considered, including: (1) individual risk assessment and gain in life expectancy, (2) value of screening and early detection methods or medical prevention, (3) disease characteristics and prognosis, and (4) anxiety and quality of life. Decisions regarding these options have to be individualized and psychological support must be offered during the period of decision and follow-up.
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PMID:Prevention and therapy for BRCA1/2 mutation carriers and women at high risk for breast and ovarian cancer. 1095 53

The tumor suppresser protein p53 is critical for guarding the genome from incorporation of damaged DNA (Lane, D. P. (1992) Nature 358, 15-16). A relevant stress that activates p53 function is UV light (Noda, A., Toma-Aiba, Y., and Fujiwara, Y. (2000) Oncogene 19, 21-31). Another well known component of the mammalian UV response is the transcription factor c-Jun (Angel, P., and Karin, M. (1991) Biochim. Biophys. Acta 1072, 129-157). We show here that upon UV irradiation p53 activates transcription of the human mismatch repair gene MSH2. Interestingly, this up-regulation critically depends on functional interaction with c-Jun. Hence, the synergistic interaction of a proto-oncogene with a tumor suppresser gene is required for the regulation of the mammalian stress response through activation of expression of MSH2.
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PMID:p53 and c-Jun functionally synergize in the regulation of the DNA repair gene hMSH2 in response to UV. 1098 93

Fifteen minute exposure of primary cultures of cerebellar granule cells to micromolar concentrations of glutamate results in apoptotic cell death. Among the intracellular events triggered by glutamate, we identified two transcriptional factors, i.e. the p50 member of the NF-kappaB family and the tumor suppressor phosphoprotein p53, that are apparently linked by a sequential trascriptional program. We found that pretreatment of the cultures with aspirin (ASA), which inhibits NF-kappaB activation, resulted in a complete prevention of glutamate-induced p53 immunoreactivity. The same results were obtained pretreating the cells with a specific p53 antisense oligonucleotide. Both ASA and p53 antisense abolished glutamate-induced apoptosis. We also found that two other proteins, the cyclin dependent kinase inhibitor p21 and DNA mismatches repair MSH2, whose encoding genes are well known target of p53, were upregulated by glutamate. On these bases, we propose NF-kappaB, p53, p21 and MSH2 as relevant contributors of the glutamate-induced pro-apoptotic pathway.
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PMID:Induction of p53 in the glutamate-induced cell death program. 1102 96

About one in eight to ten women living in Western countries will develop breast cancer during her lifetime and between 5-10% of these cases result from an inherited susceptibility to the disease. Within the past few years, a number of genes associated with a high risk of breast cancer have been identified, including BRCA1, BRCA2, TP53, PTEN, MLH1, MSH2, and STK11. The identification of these genes, together with the rapid advances in molecular genetic analyses, should improve the diagnosis and therapy of breast cancer. This article reviews the genetic basis of hereditary breast cancer, in particular the contribution of BRCA1 and BRCA2 and discusses the clinical application of this new molecular knowledge with regard to molecular testing, surveillance and prevention in women with a hereditary predisposition to breast cancer.
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PMID:Hereditary breast cancer: high risk genes, genetic testing and clinical implications. 1103 30

Molecular analysis of hereditary nonpolyposis colorectal carcinomas (HNPCC) has identified DNA mismatch repair deficiencies with resulting microsatellite instability (MSI) as a pathway of carcinogenesis that appears to be relevant for prognosis, treatment, and possibly prevention. In this study, expression of cell cycle proteins and other known prognostic markers is correlated with the microsatellite status of colorectal cancers (CRC). One hundred consecutive cases from the CRC Registry at Thomas Jefferson University were analyzed for MSI. Immunohistochemistry was performed for the mismatch repair proteins hMLH1 and hMSH2, tumor suppressor p53, apoptosis inhibitor bcl-2, cell cycle proteins p21(WAF1/CIP1), and p27 and the proliferation markers Ki-67 and topoisomerase II. High MSI (MSI-H) is significantly correlated with loss of either hMLH1 or hMSH2, presence of bcl-2, and absence of p53. p21(WAF1/CIP1) is positive in all tumors with MSI-H. Previous findings of a lower proliferation rate were confirmed with a topoisomerase II stain. Microsatellite stable (MSS) tumors generally express both MSH2 and MLH1. Other highly significant differences are positive p53 in 56% of MSS cases and negative bcl-2 in 98% of MSS cases. p27 expression is found in approximately 50% of all CRCs irrespective of the microsatellite status. MSI-H tumors follow the mutator pathway, with loss of expression of one mismatch repair protein, wild-type p53, lower proliferation, and positivity for p21(WAF1/CIP1). MSS tumors follow the suppressor pathway, characterized by p53 overexpression, higher proliferation, and absence of bcl-2 expression; p21(WAF1/CIP1) expression can be variable. These data provide a molecular basis for the clinical observation that patients with HNPCC appear to have a more favorable prognosis. HUM PATHOL 31:1506-1514.
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PMID:Colorectal carcinomas with high microsatellite instability: defining a distinct immunologic and molecular entity with respect to prognostic markers. 1115 Mar 76

Understanding the molecular mechanisms involved in the response of tumors to fractionated exposures to ionizing radiation is important for improving radiotherapy and/or radiochemotherapy. In the present study, we examined the expression of stress-related genes in an MCF-7 cell population (MCF-IR20) that has been derived through treatment with fractionated irradiation (2 Gy per fraction with a total dose of 40 Gy). MCF-IR20 cells showed a 1.6-fold increase in sensitization with dose at 10% isosurvival in a clonogenic assay, and a reduced growth delay ( approximately 15 h compared to approximately 27 h), compared to the parental MCF-7 cells treated with a single dose of 5 Gy. To determine which effector genes were altered in the MCF-IR20 cells, the expression of stress-related effector genes was measured using a filter with 588 genes (Clontech) that included major elements involved in cell cycle control, DNA repair, and apoptosis. Compared to MCF-7 cells that were not exposed to fractionated radiation, 19 genes were up- regulated (2.2-5.1-fold) and 4 were down-regulated (2.7-3.4- fold) in the MCF-IR20 cells. In agreement with the array results, 6 up-regulated genes tested by RT-PCR showed elevated expression. Also, activities of the stress-related transcription factors NFKB, TP53 and AP1 showed a 1.2-4.5-fold increase after a single dose of 5 Gy in MCF-IR20 cells compared with parental MCF-7 cells. However, when the radioresistant MCF-IR20 cell were cultured for more than 12 passages after fractionated irradiation (MCF-RV), radioresistance was lost, with the radiosensitivity being the same as the parental MCF- 7 cells. Interestingly, expression levels of CCNB1, CD9 and CDKN1A in MCF-RV cells returned to levels expressed by the parental cells, whereas the expression levels of three other genes, MSH2, MSH6 and RPA remained elevated. To determine if any of the changes in gene expression could be responsible for the induced radioresistance, CCNB1 and CDKN1A, both of which were up-regulated in MCF-IR20 cells and down-regulated in MCF-RV cells, were studied further by transfection with antisense oligonucleotides. Antisense of CCNB1 significantly reduced the clonogenic survival of MCF- IR20 cells at doses of 5 and 10 Gy, from 42% to 26% and from 5.7% to 1.0%, respectively. Antisense of CDKN1A, however, had no effect on radiation survival of MCF-IR20 cells. In summary, these results suggest that stress-related effector genes are altered in cells after treatment with fractionated irradiation, and that up-regulation of CCNB1 is responsible, at least in part, for radioresistance after fractionated irradiation.
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PMID:Effector genes altered in MCF-7 human breast cancer cells after exposure to fractionated ionizing radiation. 1126 Jun 56

Interleukin-10-deficient mice develop colitis and colorectal cancer similar to the inflammatory bowel disease associated cancer in humans. The aim of this study was to identify possible mutations of oncogenes and tumour suppressor genes involved in tumorigenesis in Interleukin-10 (IL-10)-deficient mice. Twenty colon carcinomas from IL-10-deficient mice were screened for mutations in the K-ras and p53 genes by 'cold' single-strand-conformation polymorphism. Immunohistochemical staining was performed to detect mutations in the proteins P53, APC and MSH2, and the transforming growth factor beta type II receptor. Microsatellite instability was analysed at eight chromosomal loci and plasma levels of transforming growth factor beta1 (TGF-beta1) were also measured. At 9 weeks, 14% of the animals developed colorectal cancer, and at 10-31 weeks the incidence of carcinoma was 65%. No mutations were detected in the analysed oncogene and tumour suppressor genes. Plasma TGF-beta1 levels in IL-10-deficient mice 10-31 weeks old were higher than in wild-type littermates e.g. 45.7 +/- 4.6 ng/ml versus 19.8 +/- 4.5 ng/ml (P<0.01). No alterations in K-ras, p53, APC: and Msh2 genes suggests that other genes are involved in the development of these tumours. Elevated TGF-beta1 plasma levels correspond to the high incidence of dysplasia and cancer. Normal expression of the TGF-beta II receptors hints at genetic alterations in other members of the TGF-beta receptor signal transduction pathway.
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PMID:Interleukin-10-deficient mice and inflammatory bowel disease associated cancer development. 1128 4

Defects in the human MSH2 mismatch repair system have been implicated in cellular mutagenesis, tumorigenesis, and chemotherapeutic resistance. The current studies characterized the 5' upstream proximal promoter region of the hMSH2 gene using transient transfection of A2780 ovarian cancer cells. Serial deletions of a 1.88-kb fragment of the proximal promoter region of the hMSH2 gene revealed that promoter activity was restricted to the first -281 bp. Targeted deletions within this -281 bp region coupled with specific sequence mutagenesis identified a response element for the p53 tumor suppressor protein located between -242 and -222 bp. The -242 hMSH2 p53 element is configured as a direct tandem repeat palindrome with 80% homology to the p53 consensus binding sequence. Co-transfection of an hMSH2 reporter and p53 expression vector into the p53-null cell line SK-OV-3 produced 10-fold enhanced transcription, which was lost when the -242 to -222 p53 binding site was mutated. These results clearly demonstrate the presence of a previously unidentified p53 response element in the hMSH2 proximal promoter. Its location at -242 bp upstream of the start site of transcription is distinct from two previously reported p53 sites at -447 and -416, which transactivate in Saos-2 cells (Scherer, S. J., Maier, S. M., Seifert, M., Hanselmann, R. G., Zang, K. D., Muller-Hermelink, H. K., Angel, P., Welter, C., and Schartl, M. (2000) J. Biol. Chem. 275, 37469-37473). Finally, in sharp contrast to their activity in Saos-2 cells, deletion of the -447 and -416 sites in A2780 cells had no effect on hMSH2 promoter activity. Thus, it appears that p53 regulates hMSH2 expression through multiple cell type-specific DNA response elements.
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PMID:Identification of a p53 response element in the promoter region of the hMSH2 gene required for expression in A2780 ovarian cancer cells. 1135 Sep 71


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