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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mutations in the ras gene are key events in the process of carcinogenesis; in particular, point mutations in codon 61 of exon 2 of the N-ras gene occur frequently in malignant melanoma (MM). We searched for point mutations in the N-ras gene in a large series of primary and metastatic MM from 81 different retrospectively selected patients using the very sensitive denaturing gradient gel electrophoresis technique, followed by sequencing. The classical codon 12 and codon 61 mutations were found in 21 and 17% of the cases, respectively. No codon 13 mutation was found. A novel mutation at codon 18 of exon 1, consisting of a substitution of alanine (GCA) by threonine (ACA), was found in 15% of the primary MMs but in none of the metastatic MMs. All of the other cases were free of mutations. Using microdissected cells from distinctive MM growth phases as source of DNA for mutation analysis, this particular N-ras exon 1 mutation at codon 18 was already present in the radial growth phase and preserved throughout the successive growth phases; it was also found in a dysplastic nevi in continuity with a MM, indicating a clonal relationship between both lesions. Our findings also illustrate the clonal relationship between the distinctive growth phases in MM and suggest the codon 18 mutation to occur early in MM development. The MM in patients with this mutation were significantly thinner than those without a codon 18 mutation (P = 0.0257). Statistical analysis, comparing the group of codon 18 patients with the group of patients with the classical mutations and without mutations, revealed a highly significant difference in overall outcome. The cumulative probability of developing metastasis was significantly lower for the group patients with a codon 18 mutation (P = 0.0130). We can thus conclude that this codon 18 mutation identifies a group of patients with better prognosis than patients with melanoma that harbor wild-type sequence or classical activating point mutations in codon 12 or 61. Preliminary nucleotide binding measurements could not detect a difference between wild-type Ras protein and the mutant Ras(A18T) protein. However, for a precise elucidation of the role of the N-Ras(A18T) mutant in melanoma, additional studies aimed to measure the affinity to guanine nucleotide exchange factors and GTPase-activating proteins are needed.
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PMID:A novel N-ras mutation in malignant melanoma is associated with excellent prognosis. 1140 71

Magnetic fields (MF) of 60 Hz at 1.2 microT were previously shown to inhibit the antiproliferative effect of melatonin on MCF-7 cells (Liburdy,R.P., 1993, J. Pimeal Res. 14, 89-97). In addition, three laboratories (Blackman,C.F. and Benane,S.G., 1998; Luben,R.A. and Morgan,A.P., 1998; Morris,J.E., Chrisler,W.B., Miller,D.L., Sasser,L.B. and Anderson,L.E., 1998; 20th Annual Meeting of the Bioelectromagnetics Society, At. Pete Beach, FL) independently reported results consistent with this finding. In this study, we investigated the molecular basis of the biological effects of MF using MCF-7 cells. Only 1a melatonin receptors were identified by the [125I]melatonin binding assay and RT-PCR analysis. Moreover, preceding exposures to MF of 100 microT for 3, 5 and 7 days blocked the melatonin-induced inhibition of cAMP accumulation in a time-dependent manner, while none of the melatonin receptor functions or GTPase and adenylyl cyclase activities were affected. Estrogen-evoked cell proliferation was not altered by MF either. Exposure to 1.2 microT MF exerted the same effects on the melatonin-signaling pathway as that to 100 microT. Thus, this is the first study to provide evidence that MF may cause uncoupling of signal transduction from melatonin receptors to adenylyl cyclase.
Carcinogenesis 2001 Jul
PMID:Magnetic fields (MF) of 50 Hz at 1.2 microT as well as 100 microT cause uncoupling of inhibitory pathways of adenylyl cyclase mediated by melatonin 1a receptor in MF-sensitive MCF-7 cells. 1140 47

Expression changes in subsets of genes occur in the course of altering cell fates, i.e., aging, cell death, and carcinogenesis. These changes simultaneously provide the good candidate as a biomarker for monitoring cancer. We have identified a novel human septin family gene, Bradeion, from adult brain cDNA library by a monoclonal antibody CE5. Northern blot and in situ hybridization analysis showed that Bradeion has two distinct transcripts, approximately 2.2 and 1.7 kb length (alpha and beta, respectively) mainly in brain and slightly in heart, and no expression in any fetal organs. Haplotype analysis placed the gene location at 17q23. The gene contains GTPase motifs highly conserved in the septin family genes that are essential for cytokinesis and cell separation. The transcript of beta form lacks a hydrophobic region, which suggests that this form arises from a single Bradeion gene through unique RNA splicing. Interestingly, this brain-specific Bradeion gene is also expressed in two human cancers, colorectal cancer and malignant melanoma. Ectopic expression of normal Bradeion alpha and beta transcripts were confirmed both in patients' tumor samples and in in vitro cultured human cancer cell lines. Thus the Bradeion provides valuable tools as a tumor-specific and selective marker.
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PMID:Characterization of tissue- and cell-type-specific expression of a novel human septin family gene, Bradeion. 1151 Oct 94

The mutant p21(ras) protein is a G protein produced by the point-mutated H-ras gene, and this mutant protein has been shown to cause carcinogenesis due to a reduction in its GTPase activity. However, the mechanism underlying this strange phenomenon has still not been elucidated. In our previous study, we have clarified the mechanism of the GTP-->GDP hydrolysis reaction in the wild-type p21(ras) at the atomic level and concluded that GTPase-activating protein plays a significant role in the supply of H2O molecules for the hydrolysis. The structure of the active site in the mutant is the same as that in the wild type. However, by performing molecular dynamic calculations, we found that the structure of the active site of the enzyme substrate complex in the oncogenic mutant p21(ras) continuously changes, and these continuous changes in the active site would make it difficult for the GTP-->GDP hydrolysis reaction to occur in the mutant. These findings can explain the fact that the GTPase activity in the mutant was only 15% of that in the wild type and the fact that GTPase-activating protein has no reaction-activating effect in the mutant. This is a dynamic inhibition mechanism of a vital reaction that can be explained by considering the molecular dynamics.
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PMID:Molecular dynamics simulations of Gly-12-->Val mutant of p21(ras): dynamic inhibition mechanism. 1172 Oct 9

Several markers of cell toxicity are useful as screening tests for epigenetic carcinogens. The direct effects of chemicals on ATPase and GTPase function are pertinent to the early stages of carcinogenesis. Interference with triphosphate-diphosphate exchange mechanisms may result from the interaction of carcinogens with the substrate triphosphate chain. To investigate this hypothesis, a computational chemistry programme is used in this study to investigate molecular similarity in ATPase inhibitors, carcinogens and tumour promoters, in relation to the nucleoside triphosphate chain. The results show that atoms in the investigated molecular structures superimpose on sets of oxygen atoms in the triphosphate chain with interatomic distances < 0.3A. Relative molecular similarity to the substrate triphosphate chain is discussed in terms of the established inhibitory properties of carcinogens/tumour promoters on ATPase function, the carcinogen/ tumour promoting properties of ATPase inhibitors and the prediction of carcinogenic activity from chemical structure.
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PMID:Relative molecular similarity in selected chemical carcinogens and the nucleoside triphosphate chain. 1274 74

The GTPases of the Rho family are molecular switches that play an important role in a wide range of cellular processes and are increasingly implicated in tumourigenesis. Unlike what was found for the Ras oncogenes in tumours, hardly any activating mutations have been found in the genes encoding Rho proteins. In the past, we have identified Tiam1 (T-lymphoma invasion and metastasis) as a specific activator for the Rho-like GTPase Rac. In vivo, Tiam1 deficiency protects against Ras-induced skin carcinogenesis, underscoring the consequences of deregulated signalling for the onset and progression of tumours. Thus, an important level of regulation of signalling via the Rho-like GTPases comes from the specific control of their activators. In this paper, we review what is known on the specific regulation of Tiam1 signalling towards Rac.
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PMID:Regulation of Tiam1-Rac signalling. 1282 30

Hepatitis B virus (HBV) includes an X gene (HBx gene) that plays a critical role in liver carcinogenesis. Because centrosome abnormalities are associated with genomic instability in most human cancer cells, we examined the effect of HBx on centrosomes. We found that HBx induced supernumerary centrosomes and multipolar spindles. This effect was independent of mutations in the p21 gene. Furthermore, the ability of HBV to induce supernumerary centrosomes was dependent on the presence of physiological HBx expression. We recently showed that HBx induces cytoplasmic sequestration of Crm1, a nuclear export receptor that binds to Ran GTPase, thereby inducing nuclear localization of NF-kappaB. Consistently, supernumerary centrosomes were observed in cells treated with a Crm1-specific inhibitor but not with an HBx mutant that lacked the ability to sequester Crm1 in the cytoplasm. Moreover, a fraction of Crm1 was found to be localized at the centrosomes. Immunocytochemical and ultrastructural examination of these supernumerary centrosomes revealed that inactivation of Crm1 was associated with abnormal centrioles. The presence of more than two centrosomes led to an increased frequency of defective mitoses and chromosome transmission errors. Based on this evidence, we suggest that Crm1 is actively involved in maintaining centrosome integrity and that HBx disrupts this process by inactivating Crm1 and thus contributes to HBV-mediated carcinogenesis.
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PMID:Involvement of Crm1 in hepatitis B virus X protein-induced aberrant centriole replication and abnormal mitotic spindles. 1286 Oct 14

Colorectal carcinogenesis is regarded as a multistep process resulting from accumulation of genetic alterations, including activation of protooncogenes and inactivation of tumor suppressor genes via signal transduction trigger the stage-wise progression to malignancy. The reported incidence of K-ras mutation detected in general tissue samples ranges from 21-60% in primary colorectal cancers (CRC). To assess the prevalence and spectrum of K-ras mutations in Taiwanese patients with CRC, we analyzed 65 CRC patients by polymerase chain reaction-single strand conformation polymorphism analysis, followed by direct sequencing. K-ras mutations were detected in 43.1% (28 of 65) of the tumors. The mutational hot spots were located at codons 12, 13, 15 and 20, especially with the highest frequency at codon 15. To understand whether the codon 15 mutations in CRC were associated with activation of K-ras oncogene and the alterations of its biocharacteristics, mutant K-ras genes were cloned from tumor tissues and then inserted into expression vector pBKCMV to construct the prokaryotic expression plasmid pK15MCMV. Mutant K-ras genes were expressed at high levels in E. coli and the mutant K-ras proteins were shown to be functional with respect to their well-known specific, high-affinity, GDP/GTP binding. The purified K-ras protein from E. coli was then measured for its intrinsic GTPase activity and the extrinsic GTPase activity in the presence of GTPase-activating protein for ras. We found that the extrinsic GTPase activity of the codon 15 mutant K-ras proteins (p21(K-ras15M)) in the presence of GAP is much lower than that of the wild-type K-ras protein (p21 BN), whereas the intrinsic GTPase activity is nearly the same as that of the wild-type K-ras protein. The results indicated that mutation at the codon 15 of K-ras gene indeed decreased GTPase activity in CRC, however, its association with tumorigenesis of CRC needs be clarified by further studies.
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PMID:High frequency of activated K-ras codon 15 mutant in colorectal carcinomas from Taiwanese patients. 1450 38

p120 RasGTPase-activating protein (RasGAP), the main regulator of Ras GTPase family members, is cleaved at low caspase activity into an N-terminal fragment that triggers potent anti-apoptotic signals via activation of the Ras/PI-3 kinase/Akt pathway. When caspase activity is increased, RasGAP fragment N is further processed into two fragments that effectively potentiate apoptosis. Expression of RasGAP protein and its cleavage was assessed in human lung cancer cells with different histology and responsiveness to anticancer drug-induced apoptosis. Here we show that therapy-sensitive small lung carcinoma cell (SCLC) lines have lower RasGAP expression levels and higher spontaneous cleavage with formation of fragment N compared to therapy-resistant non-small cell lung carcinoma cell (NSCLC) lines. The first RasGAP cleavage event strongly correlated with the increased level of spontaneous apoptosis in SCLC. However, generation of protective RasGAP fragment N also related to the potency of SCLC to develop secondary therapy-resistance. In response to etoposide (ET), RasGAP fragment N was further cleaved in direct dependence on caspase-3 activity, which was more pronounced in NSCLC cells. Caspase inhibition, while effectively preventing the second cleavage of RasGAP, barely affected the first cleavage of RasGAP into fragment N that was always detectable in NSCLC and SCLC cells. These findings suggest that different levels of RasGAP and fragment N might play a significant role in the biology and different clinical course of both subtypes of lung neoplasms. Furthermore, constitutive formation of RasGAP fragment N can potentially contribute to primary resistance of NSCLC to anticancer therapy by ET but also to secondary therapy-resistance in SCLC.
Carcinogenesis 2004 Jun
PMID:RasGTPase-activating protein is a target of caspases in spontaneous apoptosis of lung carcinoma cells and in response to etoposide. 1474 24

Dissemination of neoplastic cells from the primary tumor (invasion and metastasis) is a fundamentally dangerous step in multistage carcinogenesis. Recent evidence suggests that Rho GTPase-mediated signaling is linked to dissemination of cells from several different types of human tumors. The Rho family of proteins is typically associated with the regulation of cytoskeletal activity, including actin assembly, microtubule dynamics, and myosin II-dependent contractility of the actin-rich cortex. We examined the effect of overexpression of constitutively active RhoA on islands and monolayers of epithelial cells. Although newly plated cells initially formed small spread islands, there was also a significant population of cells that detached from the substrate, floated in the medium, and then could reattach to the substrate to form new colonies. Detachment of cells from transfected epithelial islands or monolayers occurred in correlation to the plane of cytokinesis after misorientation of the mitotic spindle axis. We suggest that these alterations result from Rho-induced increase of contractility of the cortex of dividing cells, which, during cytokinesis, produces a cell that has budded out of an existing layer of cells. Cell division-mediated detachment of cells from tissue structures may be an important mechanism of tumor dissemination and metastasis.
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PMID:Rho overexpression leads to mitosis-associated detachment of cells from epithelial sheets: a link to the mechanism of cancer dissemination. 1530 43


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