Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A brief review of the molecular mechanisms of nickel carcinogenesis is presented. Molecular mechanisms of nickel carcinogenesis are considered from the point-of-view of nickel-induced gene silencing by DNA hypermethylation in mammalian cells and by its ability to inhibit histone acetylation. Model systems designed to study the molecular mechanism of gene silencing are discussed.
 ...
PMID:Molecular mechanisms of nickel carcinogenesis. 1222 85

Phosphorylation of histone H3 at Ser-10 is required for maintenance of properchromosome dynamics during mitosis. AIM-1, a mammalian Ipl1/aurora kinase involved in H3 phosphorylation, is transcriptionally overexpressed in many tumor cell lines. Increased expression of the AIM-1 gene has been observed in human colorectal tumors of advanced grade and stage. Here we report that forced exogenous overexpression of AIM-1 in Chinese hamster embryo cells causes increased mitotic Ser-10 phosphorylation with concomitant induction of lagging chromosomes during mitosis. Lagging chromosomes could also be induced by transfection with mutated histone H3 (S10E), which is thought to maintain Ser-10 in the phosphorylated state. In the present study, chromosome number instability and increased tumor invasiveness were noted in constitutively AIM-1-overexpressing cells in vivo. Increased mitotic Ser-10 phosphorylation was also observed in various colorectal tumor cells with high AIM-1 expression levels. These data suggest that increased H3 histone phosphorylation as a result of AIM-1 overexpression is a major precipitating factor of chromosome instability and, thus, may play a role in carcinogenesis.
 ...
PMID:Increased mitotic phosphorylation of histone H3 attributable to AIM-1/Aurora-B overexpression contributes to chromosome number instability. 1223 80

Lunasin is a novel peptide originally identified in soybean that suppresses chemical carcinogen-induced transformation in mammalian cells and skin carcinogenesis in mice. Since the lunasin gene was cloned from soybean and the chemically synthesized form of the lunasin peptide has been used in experiments conducted so far, the isolation of lunasin from other natural sources and testing of its biological properties have not been carried out. We report here the isolation, purification, and biological assay of lunasin from barley, a newly found rich source of the peptide. The identity of lunasin was established by Western blot analysis and mass spectrometric peptide mapping of the in-gel tryptic digest of the putative protein band. Lunasin was partially purified with anion exchange and immunoaffinity chromatography. The crude and partially purified lunasin from barley suppressed colony formation in stably ras-transfected mouse fibroblast cells induced with IPTG. These fractions also inhibited histone acetylation in mouse fibroblast NIH 3T3 and human breast MCF-7 cells in the presence of the histone deacetylase inhibitor sodium butyrate.
 ...
PMID:Barley lunasin suppresses ras-induced colony formation and inhibits core histone acetylation in mammalian cells. 1235 57

Lack of a chromatin structure and histone protection makes mitochondrial DNA susceptible to oxidative damage. Suboptimal DNA repair leads to a higher frequency of mitochondrial mutations, which are associated with aging, carcinogenesis and environmental insult. The instability of the hypervariable region II of the mitochondrial genome was investigated in radiation-associated thyroid tumours, which were diagnosed in children from Belarus after the accident at the Chernobyl nuclear power plant, and from 40 sporadic thyroid tumours from Munich. Two mutations were identified in two out of 126 tumours from Belarus, and eight mutations were found in six out of 40 tumours from Munich. All mutations were deletions or insertions of C in a poly-cytidine (C7TC6) microsatellite. The mutation frequency correlated with the age of the patients at surgery. Mutations with the typical pattern of base substitutions following oxidative DNA damage were not identified.
Carcinogenesis 2002 Oct
PMID:Differential mutation frequency in mitochondrial DNA from thyroid tumours. 1280 47

Acetylation of core histones is closely linked to transcriptional activation of various genes. The acetylation levels of nucleosomal histones can be modified through a balance of histone acetyltransferases and deacetylases. To elucidate the role of histone acetylation in human gastric carcinogenesis, we studied the status of histone H4 acetylation in gastric carcinoma tissues and corresponding non-neoplastic mucosa. The status of histone acetylation was assessed by examining the expression of acetylated histone H4 through Western blotting and immunohistochemistry using an anti-acetylated histone H4 antibody. The levels of acetylated histone H4 expression were obviously reduced in 72% (13/18) of gastric carcinomas in comparison with non-neoplastic mucosa by Western blotting. In immunohistochemistry, acetylated histone H4 was clearly detected in the nuclei of both non-neoplastic epithelial and stromal cells, whereas the levels of acetylated histone H4 were heterogeneous or reduced in 66% (38/57) of gastric carcinomas and 46% (6/13) of gastric adenomas. Reduced expression of acetylated histone H4 was also observed in some areas of intestinal metaplasia adjacent to carcinomas. Reduction in the expression of acetylated histone H4 was significantly correlated with advanced stage, depth of tumor invasion and lymph node metastasis. These results suggest that low levels of histone acetylation may be closely associated with the development and progression of gastric carcinomas, possibly through alteration of gene expression.
 ...
PMID:Acetylated histone H4 is reduced in human gastric adenomas and carcinomas. 1238 81

Nickel has been shown to be an essential trace element involved in the metabolism of several species of bacteria, archea, and plants. In these organisms, nickel is involved in enzymes that catalyze both non-redox (e.g., urease, glyoxalase I) and redox (e.g., hydrogenase, carbon monoxide dehydrogenase, superoxide dismutase) reactions, and proteins involved in the transport, storage, metallocenter assembly, and regulation of nickel concentration have evolved. Studies of structure/function relationships in nickel biochemistry reveal that cysteine ligands are used to stabilize the Ni(III/II) redox couple. Certain nickel compounds have also been shown to be potent human carcinogens. A likely target for carcinogenic nickel is nuclear histone proteins. Here we present X-ray absorption spectroscopic studies of a model Ni peptide designed to help characterize the structure of the nickel complexes formed with histones and place them in the context of nickel structure/function relationships, to gain insights into the molecular mechanism of nickel carcinogenesis.
 ...
PMID:Use of XAS for the elucidation of metal structure and function: applications to nickel biochemistry, molecular toxicology, and carcinogenesis. 1242 16

Ni(II) compounds are well known as human carcinogens, though the molecular events which are responsible for this are not yet fully understood. It has been proposed that the binding of N(II) ions within the cell nucleus is a crucial element in the mechanism of carcinogenesis. The most abundant proteins in the cell nucleus are histones, and this makes them the prime candidates for this role. This article is a review of our recent studies of histone H4 models of Ni(II) binding. We analyzed the sequence of the N-terminal tail of the histone H4, Ac-SGRGKGGKGLGKGGAKRH(18)RKVL-Am, for Ni(II) binding. This site has been proposed mainly because of the potent inhibitory effect of Ni(II) on the acetylation of lysine residues near the histidine H(18), and also because of the accessibility of the H4 tail in the histone octamer. Combined potentiometric and spectroscopic studies showed that the histidine 18 acted as an anchoring binding site for metal ions in the peptide investigated. Comparison with the results for Cu(II) binding are also reported. The results allowed us to propose that the binding of Ni(II) is able to promote a secondary structure with organized side-chain orientation on the N-terminal tail of histone H4.
 ...
PMID:Molecular mechanisms in nickel carcinogenesis: modeling Ni(II) binding site in histone H4. 1242 19

The development of genomic instability is a hallmark of high-risk human papillomavirus (HPV) associated cervical carcinogenesis. We have previously shown that the HPV-16 E7 oncoprotein rapidly subverts mitotic fidelity by inducing abnormal centrosome numbers and multipolar mitotic spindles. Here we report that expression of HPV-16 E6 and E7 independently results in various mitotic abnormalities. HPV-16 E6 and E7 were each associated with unaligned or lagging chromosomal material, indicating relaxation of spindle checkpoint control. Moreover, by overwhelming checkpoint control mechanisms that may prevent cells with multiple spindle poles to enter anaphase, expression of HPV-16 E6 and E7 leads to a small but significant number of cells with altered polarity at later stages of the cell division process. In addition to changes that have the potential to give rise to numerical chromosome imbalances, we discovered that expression of HPV-16 E7 could trigger anaphase bridge formation to an extent similar to that of high-risk HPV E6. Anaphase bridges typically develop after chromosomal breaks and alterations of chromosomal structure. Further investigation of mechanisms by which HPV-16 E6 and E7 contribute to the destabilization of the host cell genome revealed that both high-risk HPV oncoproteins induce DNA damage. Moreover, expression of HPV-16 E7 was associated with an increased number of cells exhibiting nuclear foci of phosphorylated histone H2AX as well as activation of cell cycle checkpoints triggered by DNA repair. Our results therefore suggest that HPV oncoproteins are a source for both numerical and structural chromosome instability during HPV-associated carcinogenesis.
 ...
PMID:The human papillomavirus type 16 E6 and E7 oncoproteins independently induce numerical and structural chromosome instability. 1246 Sep 29

DNA methylation is essential for embryonic development and important for transcriptional repression, as observed in several biological phenomena. These include genomic imprinting, X-inactivation and carcinogenesis. The basic mechanism by which DNA methylation silences transcription is generally understood, but there is still much to be learned about how DNA methyltransferase is targeted to a specific region of the gene. Silencing by DNA methylation occurs at an early stage of carcinogenesis, when the DNA repair genes, MGMT and hMLH1, are frequently inactivated, resulting in mutations in key cancer-related genes in cells. Mice defective in Mgmt and/or Mlh1 gave clear evidence of the significant roles of these proteins in carcinogenesis. Recently, it has been demonstrated that DNA methylation is linked to histone methylation in fungi and plants, although it remains unknown whether this mechanism occurs in mammalian systems.
 ...
PMID:Gene silencing in phenomena related to DNA repair. 1248 18

It has been reported that inositol hexakisphosphate (InsP(6), phytic acid), a natural product, has an anticancer role. However, there is inadequate information regarding the mechanism by which InsP(6) exerts anticancer actions, and the effect requires relatively high concentration of the agent, both of which hinders the usage of InsP(6) as an anticancer drug. In the present study, we investigated the mechanism by which InsP(6) acts as an anticancer agent, and tried to reduce the concentration of effective InsP(6). Treatment of HeLa cells with InsP(6) at 1 mM induced apoptosis, as assessed by counting the cell number, and by Hoechst and TUNEL staining. This is probably mediated by intracellular InsP(6) itself and/or the dephosphorylated forms of metabolized InsP(6), because incubation of HeLa cells with [(3)H]InsP(6) produces dephosphorylated forms such as InsP(4) and InsP(5). Induction of apoptosis by InsP(6) was examined in two ways: inhibition of cell survival signaling and direct induction of apoptosis. Treatment of HeLa cells with tumor necrosis factor (TNF) or insulin stimulated the Akt-nuclear factor kappaB (NFkappaB) pathway, a cell survival signal, which involves the phosphorylation of Akt and IkappaB, nuclear translocation of NFkappaB and NFkappaB-luciferase transcription activity. InsP(6) blocked all these cellular events, but phosphatidylinositol 3-kinase activity was not affected. As well as inhibiting the Akt-NFkappaB pathway, InsP(6) itself caused mitochondrial permeabilization, followed by cytochrome c release, which later caused activation of the apoptotic machinery, caspase 9, caspase 3 and poly (ADP-ribose) polymerase. When InsP(6) was applied together with histone, the effective concentration to induce apoptosis was approximately 10-fold lower. These results revealed that extracellularly applied InsP(6) directly activates the apoptotic machinery as well as inhibits the cell survival signaling, probably by the intracellular delivery followed by a dephosphorylation.
Carcinogenesis 2002 Dec
PMID:Inositol hexakisphosphate blocks tumor cell growth by activating apoptotic machinery as well as by inhibiting the Akt/NFkappaB-mediated cell survival pathway. 1250 26


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>