Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The p53 gene is currently considered to function as a tumor-suppressor gene in various human malignancies. In hematologic malignancies, alterations in the p53 gene have been shown in some human leukemias and lymphomas. Although mutations in the p53 gene are infrequent in acute myelogenous leukemia (AML) patients, we show in this report that alterations in the p53 gene are frequent in myeloid leukemia cell lines. We studied alterations of the p53 gene in nine human myeloid leukemia cell lines by reverse transcriptase-polymerase chain reaction (RT-PCR), single-strand conformation polymorphism (SSCP) analysis, and direct sequencing. Expression of the p53 gene was not detected at all by RT-PCR in two of the nine cell lines. In these two cell lines, Southern blot analysis showed gross rearrangements and deletions in both of the p53 alleles. Six of the nine cell lines were found to express only mutant p53 mRNA by RT-PCR/SSCP analysis and direct sequencing, and wild-type p53 mRNA was not detected. Two of the mutant p53 mRNAs were shown to be products of abnormal splicing events induced by intronic point mutations. Taken together, eight of nine human myeloid leukemia cell lines expressed no or an undetectable amount of wild-type p53 mRNA. Three of the eight cell lines were growth factor-dependent. Our results suggest that inactivation of the p53 gene may be a common feature in myeloid leukemia cell lines and may play an important role in the establishment of these cell lines.
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PMID:Frequent mutations in the p53 gene in human myeloid leukemia cell lines. 157 49

Mouse 10T1/2 cells were transfected with combinations of T24 H-ras, human c-myc and the proline 193 mutant form of p53. The three-gene ras/myc/p53 combination was significantly more efficient than single genes or double gene combinations in inducing transformed foci in vitro. An analysis of cell lines isolated after transfections with ras, ras/myc, ras/p53 and ras/myc/p53 indicated that the last combination contained significantly higher levels of ras protein than the other combinations, produced tumors in syngeneic mice with a shorter latency period, and exhibited an increased ability to form lung tumors in an in vivo experimental metastasis assay. Synergistic interactions between ras, myc and mutant p53 genes were observed in focus formation and metastasis assays, suggesting that the action of the three oncogenes in malignant transformation occurs along separate but interactive pathways. These results support a working model of oncogene cooperativity in which alterations in myc and p53 permit elevated expression of ras, which is important in a mechanism affecting both cellular transformation in vitro and tumor dissemination in vivo.
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PMID:Evidence for synergistic interactions between ras, myc and a mutant form of p53 in cellular transformation and tumor dissemination. 162 May 51

The wild-type (wt) human tumor-suppressor gene product, p53, and its mutant form have been analysed in an in vivo system in which the inducible expression of wt p53 results in growth arrest in the G1 phase of the cell cycle. Two major pools of p53 are detected after wt p53 expression by their differential reactivity with the p53 monoclonal antibodies PAb 421 and 1801 as well as the mutant and wt-specific monoclonal antibodies PAb 240 and 1620; one pool contains wt and mutant p53 and is characterized as having a mutant conformation, whereas the other pool contains only wt p53 with a wt conformation. As G1 arrest is entered, the amount of wt p53 associated with the mutant pool decreases, such that by 12 h free wt and mutant p53 are the major pools. Two-dimensional gel analysis of the p53 pools revealed that free wt p53 is phosphorylated to a greater degree than mutant p53, which correlated with the loss of the PAb 421 epitope on wt p53. In summary, the ability of wt p53 to exert an antiproliferative effect correlates with the presence of a unique conformational state of wt p53 characterized by increased phosphorylation and the loss of both the PAb 421 epitope and association with mutant p53 pool, whereas mutant p53 is unable to assume this conformational state.
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PMID:Human wild-type p53 adopts a unique conformational and phosphorylation state in vivo during growth arrest of glioblastoma cells. 163 Aug 23

Expression of the normal p53 gene promotes cell differentiation, maturation and apoptosis. The mutant p53 gene, which does not function normally, is frequently expressed at elevated levels in tumor cells [for review see Lane, D.P. & Benchimol, S. (1990). Genes Dev., 4, 1-8]. We have analysed the expression of and mutational change in the p53 gene in the peripheral blood cells of 49 primary acute myeloid leukemia (AML) patients. The p53 protein levels were elevated in 37 patients (75%) when measured by immunoprecipitation with antibodies PAb1801 and PAb421, which recognize both normal and mutant forms of the protein. The p53 protein from 32 of these 37 patients was immunoprecipitated by PAb240, which recognizes a conformation of p53 protein associated with point mutations. However, point mutations were detected by single-stranded conformation polymorphism (SSCP) assay and direct sequencing in only three patients at codons 178, 245, 273 and 290. Growth stimulation of normal lymphocytes also generated p53 which was immunoprecipitable by PAb240. Thus, alteration of p53 conformation, rather than acquisition of point mutations, could be the mechanism underlying the increased proliferation of myeloid cells in most AML patients.
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PMID:Altered conformation of the p53 protein in myeloid leukemia cells and mitogen-stimulated normal blood cells. 163 Aug 24

Germ-line mutations in the p53 tumor suppressor gene have been observed in patients with Li-Fraumeni syndrome, brain tumors, second malignancies, and breast cancers. It is unclear whether all of these mutations have inactivated p53 and thereby provide an increased risk for cancer. Therefore, it is necessary to establish the biological significance of these germ-line mutations by the functional and structural analysis of the resulting mutant p53 proteins. We analyzed the ability of seven germ-line mutant proteins observed in patients with Li-Fraumeni syndrome, second primary neoplasms, or familial breast cancer to block the growth of malignant cells and compared the structural properties of the mutant proteins to that of the wild-type protein. Six of seven missense mutations disrupted the growth inhibitory properties and structure of the wild-type protein. One germ-line mutation retained the features of the wild-type p53. Genetic analysis of the breast cancer family in which this mutation was observed indicated that this germ-line mutation was not associated with the development of cancer. These results demonstrate that germ-line p53 mutations observed in patients with Li-Fraumeni syndrome and with second malignancies have inactivated the p53 tumor suppressor gene. The inability of the germ-line p53 mutants to block the growth of malignant cells can explain why patients with these germ-line mutations have an increased risk for cancer. The observation of a functionally silent germ-line mutation indicates that, before associating a germ-line tumor suppressor gene mutation with cancer risk, it is prudent to consider its functional significance.
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PMID:Germ-line mutations of the p53 tumor suppressor gene in patients with high risk for cancer inactivate the p53 protein. 163 Nov 37

Basal cell carcinoma (BCC) of the skin is the most common human cancer, but its molecular-genetic pathogenesis is unclear. In many other types of cancer, mutations of the tumor-suppressor gene p53 occur frequently and may lead to overexpression of a long-lived mutant form of p53 protein. In this study, overexpression of p53 protein was detected immunohistochemically in 30 (83%) of 36 specimens of BCC of the head and neck. The same regions of tumor typically were reactive both with a monoclonal antibody (PAb240) specific for the mutant protein and with one (PAb1801) directed against an epitope common to both wild-type and mutant p53 protein. Keratinocytes of chronically sun-exposed epidermis adjacent to BCCs also focally overexpressed p53 protein in the majority of cases, whereas those of sun-protected buttock skin did not. Mutation of p53 may form an important part of the pathogenetic sequence in a majority of cases of BCC.
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PMID:Overexpression of p53 protein in basal cell carcinomas of human skin. 163 67

The DNA from a wide variety of human tumors has sustained mutations within the conserved p53 coding regions. We have purified wild-type and tumor-derived mutant p53 proteins expressed from baculovirus vectors and examined their interactions with SV40 DNA. Using DNAase I footprinting assays, we observed that both human and murine wild-type p53 proteins bind specifically to sequences adjacent to the late border of the viral replication origin. By contrast, mutant p53 proteins failed to bind specifically to these sequences. SV40 T antigen prevented wild-type p53 from interacting with this region. These data show that normal but not oncogenic forms of p53 are capable of sequence-specific interactions with viral DNA. Furthermore, they provide insights into the mechanisms by which viral proteins might regulate the control of viral growth and cell division.
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PMID:Wild-type but not mutant p53 immunopurified proteins bind to sequences adjacent to the SV40 origin of replication. 164 78

The aberrant overexpression of interleukin 6 (IL-6) is implicated as an autocrine mechanism in the enhanced proliferation of the neoplastic cell elements in various B- and T-cell malignancies and in some carcinomas and sarcomas; many of these neoplasms have been shown to be associated with a mutated p53 gene. The possibility that wild-type (wt) p53, a nuclear tumor-suppressor protein, but not its transforming mutants might serve to repress IL-6 gene expression was investigated in HeLa cells. We transiently cotransfected these cells with constitutive cytomegalovirus (CMV) enhancer/promoter expression plasmids overproducing wt or mutant human or murine p53 and with appropriate chloramphenicol acetyltransferase (CAT) reporter plasmids containing the promoter elements of human IL-6, c-fos, or beta-actin genes or of porcine major histocompatibility complex (MHC) class I gene in pN-38 to evaluate the effect of the various p53 species on these promoters. Murine and human wt p53 derived from pCMVNc9 and pC53-SN3, respectively, strongly repressed the IL-6 (promoter position -225 to +13), c-fos (-711 to +42), beta-actin (-3400 to +912), and MHC (-528 to -38) promoters in serum-induced HeLa cells; additionally, IL-6 promoter/CAT transcription unit constructs induced by IL-1, phorbol ester, or pseudorabies virus were also repressed by wt human and murine p53. The murine transforming mutant p53 (pCMVc5) was less active in repressing the IL-6, c-fos, beta-actin, and MHC promoter constructs. The human p53 mutant derived from pC53-SCX3 was also less active than the wt protein in repressing the IL-6, c-fos, beta-actin, and MHC promoters, except that serum-induced IL-6/CAT expression was equally repressed by both human wt and mutant p53. In similar transient transfection experiments in HeLa cells, overexpression of the wt human retinoblastoma susceptibility gene product, RB, was found to repress the serum-induced IL-6 (-225 to +13), c-fos (-711 to +42), and beta-actin (-3400 to +912) promoters but not the PRV-induced IL-6 (-110 to +13) or the serum-induced MHC (-528 to -38) promoters. These observations identify transcriptional repression as a property of p53 and suggest that p53 and RB may be involved as transcriptional repressors in modulating IL-6 gene expression during cellular differentiation and oncogenesis.
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PMID:Repression of the interleukin 6 gene promoter by p53 and the retinoblastoma susceptibility gene product. 165 55

We examined samples of tumors of human breast, ovary, and colon of various degrees of malignancy for the expression of p53 protein, using a panel of anti-p53 antibodies and peroxidase immunohistochemistry. Of 66 tumor cases (24 cases of ovarian carcinoma, 23 cases of colon adenocarcinoma, and 19 cases of breast carcinoma), 36 (53%) showed high levels of expression of p53 using a human-specific antibody, and 16 (24%) showed high expression of a mutant form of p53. In the mutant p53-positive breast tumor samples, six (86%) were positive for HER-2/neu reactivity, compared with colon (0/4) and ovarian tumors (1/5). The pattern of p53 intracellular localization and tissue distribution, and the relationship between the expression of mutant p53 and cell differentiation, were also examined; poorly differentiated cells showed either overexpression of p53 or higher levels of mutant p53 in comparison with more normal cells.
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PMID:Immunohistochemical analysis of p53 and HER-2/neu proteins in human tumors. 168 Aug 97

To study the mechanism of p53 involvement in malignant transformation, we compared the tumor development patterns induced by a parental p53 nonproducer pre-B cell line with those by cell lines generated from this parental cell line following transfection of either wild type or mutant p53. It was found that whereas mutant p53 facilitated tumor development, expression of wild type p53 restrained tumor development. Cell lines expressing the wild type p53 induced the development of faster regressing tumors than the parental cell line. The parental p53 nonproducer and the wild type p53 producer regressor tumors underwent in vivo cell differentiation, manifested as IgG production. Mutant p53, producer cell lines, on the other hand, failed to show any immunoglobulin synthesis and gave rise to highly proliferative lethal tumors. Our results support the conclusion that these pre-B cells develop regressor tumors because they have undergone differentiation. Whereas the wild type p53 facilitates this differentiation, mutant p53 cells block it. We suggest that, in addition to inactivating the growth-suppressive activity of wild type p53, the expression of mutant p53 facilitates malignant transformation.
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PMID:Alterations in tumor development in vivo mediated by expression of wild type or mutant p53 proteins. 171 42


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