Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C1326912 (tumorigenesis)
 57,481 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previous studies in our laboratory showed nonrandom losses of chromosome 3p in association with tumorigenic transformation of SV40-immortalized human uroepithelial cells (HUC) to high grade cancers. To test the hypothesis that genes on 3p suppress HUC tumorigenesis, somatic cell hybrids were formed between nontumorigenic SV40-immortalized HUC and an isogeneic derivative transitional cell carcinoma line, MC-T16, that lost 3p on initial transformation. All hybrids were initially tumorigenically suppressed and reversion was always associated with genetic losses, including losses of 3p (Klingelhutz et al., Somatic Cell Mol. Genet., 17: 551-565, 1991). In this paper, we report that the smallest 3p region lost in a tumorigenic hybrid revertant (THR-X) in this system was an unusual interstitial deletion of 3p13----p21.2. Restriction fragment length polymorphism analysis confirmed this loss by showing that THR-X was reduced to homozygosity for D3S30, a 3p13 probe, but remained heterozygous for the distal 3p21.3 probe, D3F15S2. These data, along with our previous report identifying loss of 3p13----p14.2 as the smallest 3p region deleted in association with SV40-immortalized HUC tumorigenic transformation (Klingelhutz et al., Genes Chromosomes Cancer, 3: 346-357, 1991), provide compelling new evidence for a bladder cancer suppressor gene in the 3p13----p21.2 region.
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PMID:Loss of 3p13----p21.2 in tumorigenic reversion of a hybrid between isogeneic nontumorigenic and tumorigenic human uroepithelial cells. 131 37

Inherited susceptibility to a wide variety of neoplasias (Li-Fraumeni syndrome), has been shown in studies of one cancer-prone family, to have an intriguing association with an aberrant c-raf-1 gene and inheritance of a radioresistant phenotype in their non-cancerous skin fibroblasts. This association together with observations that DNA topoisomerases, when defective, can introduce errors into DNA and that these enzymes are perturbed in vitro by serine/threonine kinases similar to raf encoded proteins, prompted investigation of DNA topoisomerase activity of the family's fibroblasts. Since radioresistance was transferred to murine cells (NIH-3T3) when the aberrant c-raf-1 gene from this family was transfected, we also examined transformants containing this and other oncogenes. V-raf/c-myc and EJ-ras transformants were examined, the former because the family's skin fibroblasts also have 3-8-fold elevated myc expression (not apparently relevant to radioresistance) and the latter because ras, like raf, conveys radioresistance. The family members' fibroblasts and the three transfected murine lines, showed a similar perturbation of a spermidine and ATP-dependent DNA catenation activity (typical of DNA topoisomerase II). There was a significant positive correlation (r = 0.93; P = 0.0026) between the degree of activation of topoisomerase II and one measure of radioresistance (the Dq value). Relaxation of DNA supercoiling (topoisomerase I activity and other DNA nicking enzymes) was not abnormal. Cytotoxicity assays and evaluation of the influence of topoisomerase II inhibitors on DNA/protein complex formation, corroborated the existence of a qualitative topoisomerase II defect in the family's cells and transfectants. Although the contention that the qualitative topoisomerase II abnormalities observed here may be associated with malfunction is highly speculative, these findings may be relevant to the mechanism of oncogenesis, not only in this family, but with raf and ras type oncogenes.
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PMID:Aberrant DNA topoisomerase II activity, radioresistance and inherited susceptibility to cancer. 184 52

Protein tyrosine phosphorylation is associated with alterations in receptor activity, cellular proliferation and modulation of the cell cycle. Inappropriate tyrosine phosphorylation can lead to unrestrained cell growth and oncogenesis. Enzymes important in tyrosine dephosphorylation have also been described. Protein tyrosine phosphatases (PTPases) consist of two families. There is a receptor-like family of PTPases with an extracellular domain, transmembrane-spanning region and typically two repeated phosphatase domains. Proteins of the non-receptor-like family have a single catalytic phosphatase domain, show a substrate specificity for Tyr phosphate and will not hydrolyse Ser or Thr phosphate. Here we report that the vaccinia virus genome contains an open reading frame which shares amino-acid sequence identity with the PTPases. The purified protein encoded by the vaccinia virus H1 open reading frame expressed in bacteria hydrolyses substrates containing phosphotyrosine and phosphoserine. Mutagenesis of an essential Cys in the vaccinia phosphatase abolishes catalytic activity directed towards both substrates, suggesting that hydrolysis proceeds by a common mechanism. Understanding the function of the H1-encoded protein will help to define the role of the phosphatase in viral replication and pathogenesis.
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PMID:A Tyr/Ser protein phosphatase encoded by vaccinia virus. 184 23

The retinoblastoma (RB) susceptibility gene is one member of a putative "cancer suppressor gene" family in which loss of gene function is associated with tumor formation. Using antibodies generated against a trypE-RB fusion protein, we previously identified a nuclear phosphoprotein, pp110RB, as the RB gene product. Here we describe three additional polyclonal antibodies that were generated to separate epitopes of pp110RB with three synthetic peptides deduced from the RB cDNA sequence. All four antibodies could specifically recognize the same phosphoprotein in human cells. This protein was phosphorylated on serine and threonine, but not tyrosine, residues. RB homologous proteins with molecular masses of 105-128 kD were detected in other vertebrates, such as monkey, rodent, and chicken, by at least two antibodies, indicating evolutionary conservation of the RB gene. These antibodies were specific and sensitive for monitoring RB gene inactivation as demonstrated by screening several osteosarcoma and synovial sarcoma cell lines. Of nine cell lines examined, three expressed no immunoprecipitable normal RB protein. DNA rearrangement and abnormal RB mRNA were detected in two of these three cell lines, whereas RB protein was absent from one synovial sarcoma cell line in which normal-sized RB mRNA was clearly present. Therefore, direct immunoprecipitation of RB protein can reveal RB gene mutations that are undetectable by DNA and mRNA analysis. These results further support a crucial role for the RB gene in the oncogenesis of some mesenchymal tumors.
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PMID:Antibodies detecting abnormalities of the retinoblastoma susceptibility gene product (pp110RB) in osteosarcomas and synovial sarcomas. 274 Jan 44

Alveolar rhabdomyosarcoma (ARMS) is characterized cytogenetically by a t(2;13)(q35;q14) chromosomal translocation involving two transcription factor genes: PAX3 and FKHR. ARMS cells express a PAX3-FKHR fusion protein containing the complete N-terminal, DNA-binding domain of PAX3 and the C-terminus of FKHR. Recently we demonstrated that PAX3-FKHR is a more potent transcriptional activator than PAX3 despite impaired binding to canonical PAX3 binding sites. Therefore, we propose that the gene fusion results in switching of PAX3 and FKHR transactivation domains with distinct structure, potency or function. To compare the PAX3 and putative PAX3-FKHR transactivation domains, we fused C-terminal test fragments to the heterologous GAL4 DNA-binding domain and tested activation of a reporter gene co-transfected into four cell types. GAL4-PAX3 and GAL4-PAX3-FKHR were found to be potent activators exhibiting different concentration-dependent transactivation profiles and distinct structural motifs. Deletion mapping demonstrated essential acidic and/or serine/threonine-rich domains in the extreme 3' ends of their respective coding regions and positive modifying elements in adjacent 5' sequences. These data demonstrate that PAX3 and PAX3-FKHR contain structurally distinct transcriptional activation domains and suggest that a consequent difference in function is important for oncogenesis.
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PMID:Wild type PAX3 protein and the PAX3-FKHR fusion protein of alveolar rhabdomyosarcoma contain potent, structurally distinct transcriptional activation domains. 762 19

The RET proto-oncogene is expressed in human medullary thyroid carcinoma and pheochromocytoma. Recently germline mutations of the RET proto-oncogene were reported in four syndromes (MEN 2A, MEN 2B, familial medullary thyroid carcinoma and Hirschprung's disease) and somatic mutation was also found in sporadic medullary thyroid carcinoma. To determine the incidence of RET mutations in medullary thyroid carcinoma in Japan, we investigated 14 medullary thyroid carcinomas (comprising 1 case of MEN 2A, 1 case of MEN 2B, 2 cases of familial medullary thyroid carcinoma and 10 cases of sporadic). Tumors from all cases were screened by PCR-SSCP on exons 10 and 11. DNA sequencing on these exons was performed for the hereditary medullary thyroid carcinoma cases. The PCR products of exon 16 from tumor DNA were analyzed by means of Fok1 restriction enzyme digestion analysis and mutations confirmed by DNA sequencing. We found no structural abnormalities in either exon 10 or exon 11 in any of the cases examined, but in four of 10 sporadic cases we detected a common point mutation at codon 918 (ATG to ACG) in exon 16, where methionine was replaced with threonine. Our results support the theory that a point mutation of exon 16 of the RET proto-oncogene may be related to the oncogenesis of sporadic medullary thyroid carcinomas. However, further studies on the entire RET proto-oncogene are needed to clarify the relationship between its expression and thyroid tumorigenesis.
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PMID:A single missense mutation in codon 918 of the RET proto-oncogene in sporadic medullary thyroid carcinomas. 762 69

NIH 3T3 cells stably transfected with the gene encoding phosphatidylcholine-hydrolyzing phospholipase C (PC-PLC) from Bacillus cereus display a chronic elevation of intracellular diacylglycerol levels and a transformed phenotype. We have used such PC-PLC-transformed cells to evaluate the roles of the cytoplasmic serine/threonine kinases Raf-1, zeta protein kinase C (zeta PKC) and protein kinase A (PKA) in oncogenesis and mitogenic signal transduction elicited by phosphatidylcholine hydrolysis. We demonstrate here that stable expression of dominant negative mutants of both zeta PKC and Raf-1 lead to reversion of PC-PLC-transformed cells. Interestingly, expression of kinase defective zeta PKC also reverted NIH 3T3 cells transformed by the v-Ha-ras oncogene. Activation of PKA in response to elevation of cAMP levels also lead to reversion of PC-PLC-induced transformation, implicating PKA as a negative regulator acting downstream of PC-PLC. On the other hand, inhibition or depletion of phorbol ester responsive PKCs attenuated but did not block the ability of PC-PLC-transformed cells to induce DNA synthesis in the absence of growth factors. These results clearly implicate both Raf-1 and zeta PKC as necessary downstream components for transduction of the mitogenic/oncogenic signal generated by PLC-mediated hydrolysis of phosphatidylcholine and suggest, together with other recent evidence, a bifurcation in the signaling pathway downstream of PC-PLC.
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PMID:Evidence for a bifurcation of the mitogenic signaling pathway activated by Ras and phosphatidylcholine-hydrolyzing phospholipase C. 767 65

Mucins have been implicated in circumventing the defenses of the body against tumorigenesis. A better understanding of the structures of mucins may assist in the development of new therapeutic approaches. Monoclonal antibody Ea6, developed against mucins purified from xenografts of the pancreatic cancer cell line SW1990, was used to identify a new type of pancreatic cancer mucin. The following characteristics suggest that Ea6 antibody reacts with the core structure of O-linked oligosaccharides, the Tn antigen (N-acetylgalactosamine-serine/threonine): (a) increased reactivity with ovine and bovine submaxillary mucins after desialylation; (b) reactivity was inhibitable by N-acetylgalactosamine; and (c) no reactivity with blood group A oligosaccharides. Ea6 mucins from cultured SW1990 cells had lower buoyant densities (1.36 versus 1.44 g/ml) than mucins identified by another monoclonal antibody directed against SW1990 mucins, SPan-1, and were less acidic. High density and molecular mass (> or = 400 kD) secreted antigens were unaffected by sulfhydryl bond reduction. After partial deglycosylation secreted SPan-1 antigens reacted with MUC1 peptide specific antibodies, SM-3 and HMFG-2, as well as polyclonal antisera directed against deglycosylated xenograft mucins. However, Ea6 antigens did not. SW1990 cytosol also contained SPan-1 antigens with apparent molecular weights of 160,000 and 210,000 and low buoyant densities (< or = 1.22 g/ml). These reacted with monoclonal antibodies specific for the MUC1 apomucin with no prior treatment. No Ea6 reactivity was detected with this fraction. These results suggest that Ea6 antibody identifies a new population of mucins that is distinct from SPan-1 mucins.
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PMID:Multiple forms of intracellular and secreted mucins in a pancreatic cancer cell line. 767 52

Protein phosphorylation plays an important role in the regulation of cellular growth and proliferation and is thus thought to play a role in tumorigenesis. It has previously been reported that cells transformed by human cytomegalovirus (HCMV) contain two to four fold higher than normal levels of protein phosphorylation on serine and threonine residues, and two to six fold higher than normal levels of a casein kinase activity. We have now identified the major casein kinase activity found elevated in HCMV transformed cells as casein kinase type II; identification of this kinase was necessary in order to begin to define its role in HCMV mediated morphological transformation. Most of the differences in casein kinase II activity between normal and HCMV transformed cells were explained by differences in casein kinase II protein levels. This represents the first report concerning the elevation of casein kinase II activity in cells transformed by human cytomegalovirus.
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PMID:Identification of a casein kinase activity found elevated in human cytomegalovirus transformed cells. 786 67

The adenomatous polyposis coli (APC) gene is etiologically associated with familial adenomatous polyposis and gastrointestinal malignancies, but its cellular function and role in tumorigenesis are unclear. Recent reports indicate that wild-type, but not mutant, APC gene product (APC) is associated with and promotes the assembly of cytoskeletal microtubules in vitro, suggesting that this mechanism has importance in tumor development. Because other microtubule-associated proteins (MAPs) undergo phosphorylation in their normal functioning, we postulated that APC is a phosphoprotein. HCT116 cells, containing full-length APC protein, were [32P]-prelabeled, and a 300-kDa band corresponding to phosphorylated APC was immunoprecipitated using each of three different anti-APC antibodies. High voltage electrophoresis of [32P]-labeled APC showed the presence of phospho-serine and phospho-threonine residues. Further immunoprecipitation analyses showed phosphorylation of i) full-length APC in human lymphoblastoid cells and ii) carboxyl-truncated APC in SW480 and DiFi colon carcinoma cells. Thus, APC is probably a phosphoprotein in normal and malignant tissues. We hypothesize a mechanism whereby phosphorylation of APC may play a regulatory role in its interaction with microtubules. This may involve phosphorylation of (Ser/Thr)-Pro amino acid motifs in APC's basic domain. We propose that deletion of this domain disrupts APC binding to microtubules, explaining how APC mutations are linked to cancer development.
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PMID:Phosphorylation of the adenomatous polyposis coli protein and its possible regulatory effects in cells. 788 18


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