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

New data available in the literature on the role of oncogenic heterotrimeric GTP-proteins (G-proteins) in endocrine tissue carcinogenesis have been analyzed. A conclusion is made that stimulatory G-proteins coded by the gsp-oncogene are a major factor of the development of some pituitary and thyroid tumors. However, the role of the other oncogenic G-proteins in tumorigenesis remains unclear.
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PMID:[Role of oncogenic G-proteins in development of endocrine neoplasms]. 1138 51

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

Human SNAIL1 (SNAI1) protein encoded by SNAI1/SNA gene represses transcription of E-cadherin/CDH1 gene. Human SNAIL2 (SNAI2) protein encoded by SNAI2/SLUG gene induces the first phase of epithelial-mesenchymal transition (EMT), including desmosome dissociation, cell spreading, and initiation of cell separation. Here, we have identified human SNAIL3 (SNAI3) gene using bioinformatics. Human SNAI3 gene, consisting of at least three exons, spans around the nucleotide position 320214-328221 of human reference genomic contig NT_010404.8 in the reverse orientation. SNAI3 gene, was located between KIAA0233 gene and CBFA2T3 gene in human chromosome 16q24.3, a region affected in breast cancer, gastric cancer, hepatocellular carcinoma, ovarian cancer, and therapy-related myeloid leukemia with t(16;21)(q24;q22) translocation. Human SNAI3 gene was found to encode 292-amino-acid polypeptide with the N-terminal SNAG domain and five zinc finger domains. N-terminal SNAG domain was identified in zinc finger proteins SNAI1, SNAI2, SNAI3, SCRATCH (SCRT1), GFI1, and GFI1B. ATP/GTP binding site was identified in SCRT1, GFI1 and GFI1B, but not in SNAI1, SNAI2 and SNAI3. Phylogenetic analysis of human zinc finger proteins with SNAG domain revealed that SNAI1, SNAI2 and SNAI3 were more closely related. These results clearly indicate that SNAI1, SNAI2 and SNAI3 constitute a subfamily among SNAG zinc-finger proteins. Human SNAI3 mRNA was expressed in skin melanotic melanoma, lung epidermoid carcinoma, and germ cell tumor. Because SNAG zinc-finger proteins are transcriptional repressors implicated in carcinogenesis and embryogenesis, SNAI3 gene might be a potent target of pharmacogenomics in the field of oncology and regenerative medicine.
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PMID:Identification and characterization of human SNAIL3 (SNAI3) gene in silico. 1257 45

The RhoGTPases constitute a large family of small GTP binding proteins that police many sensitive crossroads in diverse cellular functions. Therefore, it would not be surprising if aberrant RhoGTPase function led to perturbed growth and differentiation, including carcinogenesis and cancer progression. The evidence for a causative connection between RhoGTPases and primary human cancers is still weak but there are increasing findings to support this link. An appreciation of this connection is timely and important to alert readers to the possibilities of new disease mechanisms and new ways to diagnose and treat cancer.
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PMID:RhoGTPases and their role in cancer. 1272 21

The use of botanical supplements has received immense interest in recent years to protect human skin from adverse biological effects of solar ultraviolet (UV) radiation. The polyphenols from green tea are one of them and have been shown to prevent photocarcinogenesis in animal models but their mechanism of photoprotection is not well understood. To determine the mechanism of photoprotection in in vivo mouse model, topical treatment of polyphenols from green tea (GTP) or its most chemopreventive constituent (-)-epigallocatechin-3-gallate (EGCG) (1 mg/cm(2) skin area) in hydrophilic ointment USP before single (180 mJ/cm(2)) or multiple UVB exposures (180 mJ/cm(2), daily for 10 days) resulted in significant prevention of UVB-induced depletion of antioxidant enzymes such as glutathione peroxidase (78-100%, P < 0.005-0.001), catalase (51-92%, P < 0.001) and glutathione level (87-100%, P < 0.005). Treatment of EGCG or GTP also inhibited UVB-induced oxidative stress when measured in terms of lipid peroxidation (76-95%, P < 0.001), and protein oxidation (67-75%, P > 0.001). Further, to delineate the inhibition of UVB-induced oxidative stress with cell signaling pathways, treatment of EGCG to mouse skin resulted in marked inhibition of a single UVB irradiation-induced phosphorylation of ERK1/2 (16-95%), JNK (46-100%) and p38 (100%) proteins of MAPK family in a time-dependent manner. Identical photoprotective effects of EGCG or GTP were also observed against multiple UVB irradiation-induced phosphorylation of the proteins of MAPK family in vivo mouse skin. Photoprotective efficacy of GTP given in drinking water (d.w.) (0.2%, w/v) was also determined and compared with that of topical treatment of EGCG and GTP. Treatment of GTP in d.w. also significantly prevented single or multiple UVB irradiation-induced depletion of antioxidant enzymes (44-61%, P < 0.01-0.001), oxidative stress (33-71%, P < 0.01) and phosphorylation of ERK1/2, JNK and p38 proteins of MAPK family but the photoprotective efficacy was comparatively less than that of topical treatments of EGCG and GTP. Lesser photoprotective efficacy of GTP in d.w. in comparison with topical application may be due to its less bioavailability in skin target cells. Together, for the first time a cream based formulation of green tea polyphenols was tested in this study to explore the possibility of its use for the humans, and the data obtained from this in vivo study further suggest that GTP could be useful in attenuation of solar UVB light-induced oxidative stress-mediated and MAPK-caused skin disorders in humans.
Carcinogenesis 2003 May
PMID:Treatment of green tea polyphenols in hydrophilic cream prevents UVB-induced oxidation of lipids and proteins, depletion of antioxidant enzymes and phosphorylation of MAPK proteins in SKH-1 hairless mouse skin. 2972 76

A gene or genes on chromosome 8p22-23 have been implicated in prostate carcinogenesis by the observation of frequent deletions of this region in prostate cancer cells. More recently, two genetic linkage studies in hereditary prostate cancer (HPC) families suggest that germline variation in a gene in this region may influence prostate cancer susceptibility as well. DLC1 (deleted in liver cancer), a gene in this interval, has been proposed as a candidate tumor suppressor gene because of its homology (86% similarity) with rat p122 RhoGAP, which catalyzes the conversion of active GTP-bound rho complex to the inactive GDP-bound form, and thus suppresses Ras-mediated oncogenic transformation. A missense mutation and three intronic insertions/deletions in 126 primary colorectal tumors have been previously identified. However, there are no reports of DLC1 mutation screening in prostate tumors or in germ line DNA of prostate cancer patients. In this study, we report the results of the first mutation screen and association study of DLC1 in genomic DNA samples from hereditary and sporadic prostate cancer patients. The PCR products in the 5' UTR, all 14 exons, exon-intron junctions, and 3' UTR were directly sequenced in 159 HPC probands. Eight exonic nucleotide polymorphisms (SNPs) were identified, only one of which resulted in an amino acid change. Twenty-three other SNPs were identified in intronic regions. Seven informative SNPs that spanned the complete DLC1 gene were genotyped in an additional 249 sporadic cases and 222 unaffected controls. No significant difference in the allele and genotype frequencies were observed among HPC probands, sporadic cases, and unaffected controls. These results suggest that DLC1 is unlikely to play an important role in prostate cancer susceptibility.
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PMID:Evaluation of DLC1 as a prostate cancer susceptibility gene: mutation screen and association study. 1287 22

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

The mouse skin model of carcinogenesis has been instrumental in our appreciation of the multistage nature of carcinogenesis. In this system, tumor promotion is a critical step in the generation of tumors and is usually achieved by treatment with the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA). Although it is generally assumed that protein kinase C (PKC) is the sole receptor for TPA in this system, we sought to evaluate whether non-PKC pathways could also contribute to the effects of phorbol esters in skin. We documented expression of the high affinity non-PKC phorbol ester receptor and Ras activator RasGRP1 in mouse primary keratinocytes. Overexpression of RasGRP1 in keratinocytes increased the level of active GTP-loaded Ras. TPA treatment further elevated this Ras activation in a PKC-independent manner and induced the translocation and down-regulation of RasGRP1. Overexpression of RasGRP1 in keratinocytes also caused apoptosis. Finally, induction of keratinocyte differentiation by elevation of extracellular calcium suppressed expression of endogenous RasGRP1, whereas overexpression of RasGRP1 inhibited expression of the differentiation markers keratins 1 and 10 induced by high calcium in the medium. Taken together, our results demonstrate that RasGRP1 is an additional diacylglycerol/phorbol ester receptor in epidermal keratinocytes and suggest that activation of this novel receptor may contribute to some of the phorbol ester- and Ras-mediated effects in mouse epidermis.
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PMID:RasGRP1 represents a novel non-protein kinase C phorbol ester signaling pathway in mouse epidermal keratinocytes. 1453 95

K-ras is frequently mutated in lung adenocarcinomas. Recent discovery that wild-type K-ras is tumor suppressive in the lung raises a question: how is mutant K-ras aggressively oncogenic? We hypothesized that mutant K-ras might lead to generation of reactive oxygen species (ROS) and DNA damage, contributing to malignant transformation. We stably transfected human mutant K-ras(V12) into non-transformed peripheral mouse lung epithelial cells (E10 line). Constitutively active mutant K-ras(V12) in E10 cells led to a highly significant (P < 0.001) increased level of peroxides, and a corresponding increase in the amount of DNA strand-break damage, compared with the parental line E10 and the vector control. Levels of superoxide were not increased, suggesting a direct source of peroxides, such as cyclooxygenase-2 (COX-2). COX-2 protein and activity measured as prostaglandin E(2) level were up-regulated in cells expressing mutant K-ras(V12); COX-2 activity correlated with K-ras activity (K-ras p21-GTP). Both peroxide generation and DNA single strand breaks were significantly reduced by pre-treatment with COX-2-specific inhibitor SC 58125, confirming COX-2 as the source of the ROS. COX-2 has been repeatedly implicated in lung cancer, and is known to be regulated by ras and to release ROS. Our data suggest that up-regulation of COX-2, with a consequent increase in peroxides and DNA damage, contributes to the dominant oncogenicity of mutant K-ras.
Carcinogenesis 2004 Nov
PMID:Mutant K-rasV12 increases COX-2, peroxides and DNA damage in lung cells. 1528 81

Recurrence and metastasis are commonly associated with poor prognosis of hepatocellular carcinoma (HCC). Therefore, a better understanding of molecular mechanisms involved in HCC metastasis may lead to more effective treatment for HCC patients. Rac plays important roles in cytoskeletal reorganization leading to cell motility in renal and breast carcinomas. However, the role of Rac is controversial in tumors and has not been studied in HCC. The aim of this study was to investigate the importance of the Rac signaling pathway in HCC cell motility and the anti-metastatic potential of FTY720. Recently a pair of HCC cell lines from a primary tumor (H2P) and its matched metastasis (H2M) was established. These two cell lines provide a useful tool for the study of HCC metastasis. The results show that the Rac signaling pathway is activated in the metastatic HCC cell line (H2M) compared with the primary HCC cell line (H2P). FTY720 specifically suppressed H2M cell motility by down-regulation of the Rac-GTP level through inhibition of phosphoinositide 3-kinase activity. To conclude, this study is the first to demonstrate an essential role of Rac signaling pathway activation in HCC metastasis and suppression of cell motility by FTY720 through blocking of the Rac pathway.
Carcinogenesis 2005 Mar
PMID:Significance of the Rac signaling pathway in HCC cell motility: implications for a new therapeutic target. 1560 94


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