Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Spontaneous and radiation-induced apoptosis in three lung carcinoma cell lines (U-1285, U-1906 and U-1810) with previously characterised intrinsic radiosensitivities (RS) was assessed by TUNEL-staining, detection of DNA laddering and cleavage of poly-(ADP-ribose) polymerase (PARP). Spontaneous apoptosis was detected at a high level in the radiosensitive U-1285, at an intermediate level in U-1906 and not detected in the radioresistant U-1810 cell line. Radiation-induced apoptosis, assessed by TUNEL assay, was present in U-1285 and U-1906 cells but not in U-1810 cells. To explain these findings, expression of Bcl-2, Bax, c-Myc and RB protein and mutations of the p53 gene were analysed. The ratio Bcl-2/Bax was higher in U-1810 cells compared with U-1285 and U-1906 cells. Overexpression of c-Myc and loss of RB was found in U-1285 cells whereas both U-1906 and U-1810 cells expressed RB and showed lower c-Myc expression. Analysis with sequencing of all p53 exons disclosed mutations in all three cell lines. Thus, apoptosis was a p53 independent process in U-1285 and U-1906 cells. RB loss and overexpression of c-Myc may enhance apoptosis in U-1285 cells. Our data suggest that spontaneous apoptosis may correlate with RS in SCLC.
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PMID:Spontaneous and radiation-induced apoptosis in lung carcinoma cells with different intrinsic radiosensitivities. 961 7

Medullary thyroid carcinoma (MTC) is a tumor of parafollicular cells of the thyroid gland. It has served as a useful experimental model for the study of tumor proliferation and differentiation. Although recent studies have identified the gene involved in familial forms of MTC, little is known about the molecular pathogenesis of the sporadic variants of this tumor. It has become increasingly clear that deregulation of programmed cell death is a critical component in multistep tumorigenesis. The present investigation was undertaken to determine whether similar molecular events occur in human MTC. Eighteen MTCs from 18 patients (including 12 sporadic and six familial cases and one metastatic lymph gland) and a MTC cell line (TT cells) were used in this study for detecting the expression of apoptosis-regulatory genes bcl-2, bax, c-myc, and p53. Immunohistochemical results showed that all MTC tumor samples displayed Bcl-2 and c-Myc immunoreactivity, whereas only 4 and 2 tumors showed a minority of cells positive for Bax and p53, respectively. Western and Northern blotting showed high levels of 26-kd Bcl-2 protein and bcl-2 transcript. The co-expression of Bcl-2 and c-Myc was also detected in the TT cells by indirect fluorescence immunohistochemistry and Western blotting. Moreover, Bcl-2 immunoreactivity was also found in C-cell hyperplasia from familial patients indicating that expression of this oncogene may represent an early event in the pathogenesis of MTC. The present study suggests that deregulation of programmed cell death may be a critical component in multistep tumorigenesis of MTC and that the frequent expression of the Bcl-2 oncoprotein in these tumors may contribute to their pathogenesis. The genetic complementation of simultaneously deregulated bcl-2 and c-myc may be implicated in the multistep tumorigenesis of human MTC.
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PMID:Bcl-2 and c-Myc, but not bax and p53, are expressed during human medullary thyroid tumorigenesis. 962 44

Numerous factors trigger or repress apoptosis (genetically mediated individual cell death). The details of signal transduction pathways and regulation of apoptosis by numerous oncogene and tumor suppressor gene products are not fully understood. Bcl-2 inhibits apoptosis induction by a variety of stimuli. Caspases are the basic effectors of apoptosis, leading ultimately to fragmentation of DNA, at which stage apoptosis can be identified. Apoptosis affects scattered individual cells that have extremely dense nodular, beaded, or crescentic chromatin, and differs morphologically, biochemically, and topographically from necrosis. Apoptosis is a negative growth-regulating mechanism in cancer, and its extent varies with tumor type. Apoptosis reflects tumor cell kinetics; aggressive tumors often show conspicuous apoptosis, and there are significant linear correlations between apoptotic and mitotic indices in many tumor types. The relative importance of p53, c-Myc, Rb, and the Bcl-2 homologs in the regulation of apoptosis in different human cancers is not clear. Further pathologic investigations on apoptosis in human cancer are needed to reaffirm recent experimental findings and to explain more fully the regulation and biological significance of apoptosis in vivo.
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PMID:Apoptosis: basic concepts and potential significance in human cancer. 964 97

We have examined defects in mammary development and tumorigenesis in a transgenic model expressing the c-myc gene under the MMTV-LTR promoter. The stochastic tumors which arise from hyperplastic ductal and lobular lesions in this model are characterized by high rates both of apoptosis and of chromosomal instability. Since the p53 gene product is thought to be central in the maintenance of genomic integrity, in part due to its ability to induce apoptosis in cells harboring DNA damage, we examined its expression and possible mutation. Initially, we observed that unmutated p53 is strongly expressed in premalignant mammary glands and in mammary tumors derived from the MMTV-c-myc strain. We then mated the MMTV-myc strain to a p53-deficient strain as a means of examining the effect of this lesion on mammary development and tumorigenesis in the context of c-myc overexpression. A lack of both p53 alleles in the presence of c-myc overexpression resulted in a dramatic hyerplastic alteration in mammary gland development. Specifically, in female bitransgenic MMTV-c-myc/p53 null mice (MMTV-myc/p53(-/-)), lobular hyperplasias were observed at almost every ductal end bud as early as 32 days of age. In contrast, only mild ductal and lobular hyperplasias were seen in MMTV-myc mice that contained both p53 alleles (MMTV-myc/p53(+/+)); an intermediate phenotype occurred in mice with a single intact (MMTV-myc/p53(+/-)) p53 allele. Mammary carcinomas arose with a high frequency in MMTV-myc/p53(+/-) mice; the tumors were comparable in frequency, histology and apoptotic index to the tumors in MMTV-myc/p53(+/+) mice. Also, as previously observed (Elson et al., 1995), lymphomas arose with extremely short latency in MMTV-myc/p53(-/-) mice, precluding study of the fate of their hyperplastic mammary lesions in situ. The frequency of p53 mutations in MMTV-myc/p53(+/+) and MMTV-myc/p53(+/-) mammary tumors and in cell lines derived from these tumors was examined by direct sequencing. No point mutations or deletions in p53 were observed in mammary tumors or cell lines from either genotype. Finally, a detailed chromosomal analysis using multicolor spectral karyotyping (SKY) revealed that there were multiple chromosomal alterations in the c-myc-overexpressing cells that contained either one or two unmutated p53 alleles. Variable ploidy changes, a common translocation of chromosome 11, and other chromosomal aberrations were observed. Our data thus support an interaction between c-Myc and p53 in mammary development, but suggest that loss of p53 is required neither for c-myc-dependent tumorigenesis nor for c-myc-dependent chromosomal instability.
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PMID:Myc/p53 interactions in transgenic mouse mammary development, tumorigenesis and chromosomal instability. 965 42

Scatter factor (SF) (hepatocyte growth factor) is a cytokine that may play a role in human breast cancer invasiveness and angiogenesis. We now report that SF can block the induction of apoptosis by various DNA damaging-agents, including cytotoxic agents used in breast cancer therapy. SF protected MDA-MB-453 human breast cancer cells, EMT6 mouse mammary tumor cells and MDCK renal epithelial cells against apoptosis induced by adriamycin (ADR), X-rays, ultraviolet radiation, and other agents. Protection was observed in assays of DNA fragmentation, cell viability (MTT), and clonogenic survival. Protection of MDA-MB-453 cells against ADR was dose- and time-dependent; maximal protection required pre-incubation with 75-100 ng/ml of SF for 48 h or more. Protection required functional SF receptor (c-Met), but was not dependent on p53. Western blotting analysis revealed that pre-treatment of MDA-MB-453 cells with SF inhibited the ADR-induced decreases in the levels of Bcl-XL, an anti-apoptotic protein related to Bcl-2; and the dose-response and time course characteristics for SF-mediated increases in the Bcl-XL protein levels of ADR-treated cells were consistent with the degrees of protection against apoptosis observed under the same conditions. Furthermore, Bcl-XL levels were not down-regulated by ADR in MDA-MB-231 breast cancer cells, consistent with the finding that SF failed to protect these cells against ADR, despite the fact that they contain functional c-Met receptor. In contrast to Bcl-XL, SF blocked ADR-induced increases in c-Myc and inhibited the expression of p21WAF1/CIP1 and of the BRCA1 protein in MDA-MB-453 cells. However, SF did not cause significant changes in the cell cycle distribution of ADR-treated cells. These findings suggest that SF-mediated protection of human breast cancer cells may involve inhibition of one or more pathways required for the activation of apoptosis and may particularly target the anti-apoptotic mitochondrial membrane pore-forming protein Bcl-XL as a component of the protective mechanism. By implication, the accumulation of SF within human breast cancers may contribute to the development of a radio- or chemoresistant phenotype.
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PMID:Scatter factor protects epithelial and carcinoma cells against apoptosis induced by DNA-damaging agents. 967 97

The myc proto-oncogenes are transcription factors that directly regulate the expression of other genes, by binding to the specific DNA sequence, CACGTG. Among the target genes for c-Myc regulation are ECA39, p53, ornithine decarboxylase (ODC), alpha-prothymosin and Cdc25A. In this study we examined the involvement of c-Myc target genes in human oncogenesis induced by c-myc or N-myc. In MCF-7 breast cancer cells, the induction of c-myc expression by estrogen was followed by the induction of all the Myc targets that we examined, indicating that those genes can serve as c-Myc targets in human oncogenesis. Moreover, in breast tumors exhibiting c-myc overexpression, several Myc targets were also overexpressed. A clear correlation between the expression of c-myc and its targets was also detected in Burkitt's lymphomas, which involve a specific translocation of c-myc gene, but not in other lymphoma cells. Yet, in cells derived from a neuronal origin the pattern of expression of Myc targets was more complex. In a neuroepithelioma cell line that overexpresses c-myc, only some targets were expressed. In addition in neuroblastomas, in which N-myc is amplified and overexpressed, only ODC was overexpressed in all cell lines, while all other target genes were expressed in only some of the cell lines. The more complex expression pattern found for the Myc targets in neuroblastomas suggests that genes that were identified originally as targets for c-Myc regulation may be regulated by N-Myc, but other cell specific factors are also needed for transcription of the target genes.
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PMID:Involvement of Myc targets in c-myc and N-myc induced human tumors. 967

Relatively little is known about molecular genetic events that participate in the genesis and progression of hemangiopericytoma. In this study, we describe two cases of hemangiopericytoma accompanied by severe hypoglycemia. Tumor cells from patient 1 exhibited insulin-growth factor I (IGF I) and insulin-like growth factor I receptor (IGF IR) mRNA transcripts. Tumor cells from patient 2 exhibited IGF II, IGF IR and IGF binding proteins 1-3 mRNA. Serum from patient 2 contained IGF II, mostly in a large molecular form ("big" IGF II); the IGF II level did not change after the tumor removal. The presence of IGF IR in tumor cells was confirmed by immunoprecipitation with antibodies that recognize human IGF IR subunit (visualized as a 460-kDa band). The hemangiopericytoma cells derived from patient 1 expressed 210000 IGF I receptors/cell. Specific binding of IGF I to the tumor cell membrane fraction was higher in tissue from patient 1, while the tissue of patient 2 showed relatively low IGF I binding. In contrast, IGF II binding was much higher in tissue from patient 2. Both tumor tissues showed positive immunostaining for c-Jun; one tumor showed strong immunostaining for c-Myc, H-Ras and p53, while the other exhibited strong reaction with H-Ras antibodies only. No loss of the heterozygosity at the genes APC, NFI and nm23-H1 loci in tumor tissue obtained from patient 1 was found. In effect, our results suggest multiple molecular genetic changes in hemangiopericytoma -- activation of some oncogenes and the IGF growth factor family. IGF ligands together with IGF IR could be responsible for hypoglycemia and perhaps the transformed phenotype.
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PMID:Molecular pathology of hemangiopericytomas accompanied by severe hypoglycemia: oncogenes, tumor-suppressor genes and the insulin-like growth factor family. 969 37

Hereditary ovarian cancers associated with germline mutations in either BRCA1 or BRCA2 were studied to determine whether somatic mutation of the P53 gene is required for BRCA-linked ovarian tumorigenesis and further, whether the spectrum of additional somatic molecular genetic alterations present in these tumors differs from that known to exist in sporadic ovarian cancers. Forty tumors, 29 linked to BRCA1 and 11 linked to BRCA2, were examined for mutational alterations in P53, K-RAS, ERBB-2, C-MYC, and AKT2. The presence of a P53 mutation in 80% of these cancers indicates that P53 mutation is common but not required for BRCA-linked ovarian tumorigenesis; notably, a significantly higher proportion of the P53 mutations in BRCA2-linked cancers were deletions or insertions compared with the more typical spectrum of missense mutations seen in BRCA1-linked cancers. Additionally, BRCA-linked ovarian carcinomas seem to develop through a unique pathway of tumorigenesis that does not involve mutation of K-RAS or amplification of ERBB-2, C-MYC, or AKT2.
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PMID:Molecular genetic characterization of BRCA1- and BRCA2-linked hereditary ovarian cancers. 969 40

c-Myc is a nuclear protein with important roles in cell transformation, cell proliferation, and gene transcription. It has been previously shown that a 14-amino acid (aa) modified peptide (H1-S6A,F8A) derived from the helix 1 (H1) carboxylic region of c-Myc can interfere in vitro with specific c-Myc DNA binding. Here, we have linked the above Myc-derived 14-aa peptide to a 16-aa sequence from the third helix of Antennapedia (Int). It has been repeatedly reported that this 16-aa Antennapedia peptide is able to cross mammalian cell membranes and to work as a vector for short peptides. Using fluorescent (dansylated or rhodaminated) peptides, we have shown that the fusion peptide with the Antennapedia fragment (Int-H1-S6A,F8A) but not the c-Myc derived fragment alone (H1-S6A,F8A) was capable of internalization inside MCF-7 human breast cancer cells. Int-H1-S6A,F8A and H1-S6A,F8A were the only two peptides capable of inhibiting coimmunoprecipitation of the c-Myc/Max heterodimer in vitro. We have treated (continuously for 10-11 days) MCF-7 cells with four different peptides: Int, H1-S6A,F8A, Int-H1-S6A,F8A, and Int-H1wt [a peptide differing from Int-H1-S6A,F8A by 2 aa (S6 and F8) in the H1 region]. In intact MCF-7 cells, Int-H1-S6A,F8A was the only active peptide capable of inducing the following biological effects: (a) inhibition of cloning efficiency on plates; (b) inhibition of cell growth and induction of apoptosis in subconfluent/confluent cells; and (c) inhibition of transcription of two c-Myc-regulated genes (ODC and p53). Int-H1-S6A,F8A was active in the 1-10 microM range. Int-H1-S6A,F8A may represent a lead molecule for peptidomimetic compounds that have a similar three-dimensional structure but are more resistant to peptidases and, therefore, suitable for in vivo treatment of experimentally induced tumors.
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PMID:Inhibition of cancer cell growth and c-Myc transcriptional activity by a c-Myc helix 1-type peptide fused to an internalization sequence. 972 75

We have investigated several molecular events that occur during the process of tamoxifen-induced apoptosis in human breast carcinoma cells. We show that the treatment of either MCF-7 (containing wild-type p53) or MDA-MB-231 cells (containing mutant p53) with tamoxifen resulted in apoptotic nuclear changes and an increase in the pre-G1 apoptotic population. This was accompanied by activation of the caspase enzymes, as evidenced by specific cleavage of poly(ADP-ribose) polymerase and retinoblastoma (RB) protein. The RB protein was cleaved at both an interior and carboxyl terminus cleavage site. In addition, dephosphorylation of RB was found at an early stage of tamoxifen-induced apoptosis in both cell lines. However, neither induction of p53 in MCF-7 cells nor induction of p21 in either cell line was detected, suggesting that tamoxifen-induced RB dephosphorylation and apoptosis are independent of the p53/p21 pathway. We also observed an increase in levels of the pro-apoptotic Bax protein, the inhibitory cytokine TGF-beta1 and the transcription factor c-Myc in tamoxifen-treated MDA-MB-231 cells, suggesting the possible involvement of these proteins during apoptosis in this system.
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PMID:p53-independent dephosphorylation and cleavage of retinoblastoma protein during tamoxifen-induced apoptosis in human breast carcinoma cells. 975 Dec 62


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