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

A potential chemopreventive action of pravastatin (Pr), a 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor, on colon carcinogenesis was evaluated in F344 rats. All rats at 7 weeks of age received an intrarectal dose of 2 mg of N-methyl-N-nitrosourea 3 times weekly for 2 weeks in experiment I (2 groups of 16 rats each), and for 3 weeks in experiment II (4 groups of 30 rats each). They were given drinking water containing 0 ppm (control) or 200 ppm Pr during weeks 1 to 40 in experiment I, and containing 0 ppm (control), 25 ppm, 5 ppm and 1 ppm Pr during weeks 4 to 40 in experiment II. The body weight gains, and food and water intakes were similar in all the groups. The incidence of colon carcinomas at termination of the experiment at week 40 was not different in the 200 ppm Pr and control groups in experiment I (63% vs. 69%), while it was significantly lower in the 25 ppm and 5 ppm groups, but not in the 1 ppm Pr group, compared with the control group in experiment II (50%, 48%, and 77% vs. 80%). This inhibitory effect of Pr against colon carcinogenesis was not related to the cholesterol-lowering effect of this agent. We postulate that Pr inhibits the promotion stage of colon carcinogenesis, perhaps through modulation of cholesterol synthesis in situ in the colonic mucosa, thereby suppressing farnesyl isoprenylation of growth-regulating proteins such as p21 ras.
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PMID:Chemoprevention by pravastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor, of N-methyl-N-nitrosourea-induced colon carcinogenesis in F344 rats. 879 85

Transcription elongation factors assist RNA polymerase II through transcriptional blockages. The human transcriptional elongation factor SII or Trascription Elongation Factor A (TCEA) releases RNA polymerase II from transcriptional arrest and is encoded by a 2.5-kb intronless gene. Using PCR primers, verified by RT-PCR to amplify the authentic, transcriptionally active SII gene, this locus was mapped to human chromosome 3 by examination of a human/rodent somatic cell hybrid panel. PCR analysis of somatic cell hybrids with chromosome 3 translocations and FISH studies utilizing a human YAC clone containing the SII gene further refine the map position of this locus to human chromosome 3p22 --> p21.3. Since another elongation factor, SIII, has been implicated in human carcinogenesis and since the interval within which the human SII gene maps is frequently deleted in certain cancers, elongation factor SII may therefore be considered a candidate gene for human malignancies involving 3p22 --> p21.3.
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PMID:Transcription elongation factor SII (TCEA) maps to human chromosome 3p22 --> p21.3. 881 34

To investigate the effect of p53 tumor suppressor gene loss in the mouse skin model of multistage carcinogenesis, p53 knockout mice, generated by gene targeting (p53 -/-), were mated to transgenic mice expressing v-rasHa (HK1.ras), v-fos (HK1.fos), or human transforming growth factor alpha+HK1.TGFalpha) exclusively in the epidermis, by means of a keratin K1-based targeting vector (HK1). HK1-p53 transgenic progeny expressing wild-type p53 alleles (p53 +/+) or hemizygous for the p53 knockout allele (p53+/-) were identical to parental HK1 lines and exhibited neonatal epidermal hyperplasia or wound-associated hyperplasia in adults, together with spontaneous or 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced benign papillomas. Mating to p53-/- did not lead to the expected tumorigenesis in adults. Instead, whereas HK1.ras or HK1.TGFalpha transgenic mice null for p53 (HK1.ras-p53-/- and HK1.TGFalpha-p53-/-, respectively) retained the neonatal epidermal hyperplasia phenotype, in adults, spontaneous and TPA-promoted papilloma formation was blocked. Similarly, wound-associated epidermal hyperplasia/hyperkeratosis, a hallmark of adult HK1.fos phenotypes, was completely absent in HK1.fos-p53 -/- mice. Histological, immunofluorescence, and bromodeoxyuridine labeling analysis of neonatal or adult epidermis in HK1-p53 transgenic genotypes +/+, +/-, and -/- for p53 revealed no obvious differences in morphology, expression of keratinocyte differentiation markers, or mitotic index attributed to p53 loss. To determine whether the paradoxical absence of papillomas centered on up-regulation of p53 target genes, WAF1/CIP1/p21 RNA expression levels were examined in TPA promotion experiments. WAF1/CIP1/p21 expression increased in response to TPA promotion in all HK1-p53 transgenic genotypes regardless of p53 status. However, in HK1-p53 null genotypes, although TPA-induced, p53-independent WAF1/CIP1/p21 expression was observed, no large increase in expression was associated with the observed paradoxical tumorigenesis block. These data suggest that epidermis is somewhat resistant to the neoplastic effects of p53 loss, possibly possessing several compensatory systems. Alternatively, there may be a requirement forp53 expression in response to TPA or a wound-promotion stimulus in mouse epidermis.
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PMID:Paradoxical tumor inhibitory effect of p53 loss in transgenic mice expressing epidermal-targeted v-rasHa, v-fos, or human transforming growth factor alpha. 881 35

The LEC rat is an inbred mutant strain which spontaneously develops liver injury and subsequent liver cancer. Liver injury in LEC rats has recently been shown to be closely related to abnormal copper accumulation in the liver. Previously, we reported that LEC rat hepatocytes lose their growth potential, probably allowing selective growth of preneoplastic cells. In this study, to elucidate the effects of copper accumulation on the growth activity of LEC rat hepatocytes, we examined the growth activity and the expression of p53 and p21(waf 1/cip 1) in the livers of LEC rats fed on either a control or a low-copper diet. Potential for cell proliferation of hepatocytes obtained from normal diet fed LEC rats was almost comparable to that of the cells from age-matched Sprague-Dawley (SD) rats. Northern blot analysis showed that the expression of p53 and p21(waf 1/cip 1) was significantly high in the livers of LEC rats fed a control diet, while the expression of p53 and p21(waf 1/cip 1) in the LEC rats fed a low-copper diet was as low as that of SD rat livers. Western blot analysis consistently showed that the amount of p21(waf 1/cip 1) bound to the nuclear matrix scaffold of the LEC rat liver was reduced by feeding a low-copper diet. These findings suggest that abnormal accumulation of copper induced the expression of p53 and p21(waf 1/cip 1), resulting in the inhibition of cell proliferation of LEC rat hepatocytes.
Carcinogenesis 1996 Oct
PMID:Abnormal accumulation of copper in LEC rat liver induces expression of p53 and nuclear matrix-bound p21(waf 1/cip 1). 889 83

Eukaryotic cell cycle progression is controlled by a host of cyclin/cyclin-dependent kinases (Cdks), that are themselves regulated by multiple factors, including a group of small cyclin-Cdk inhibitor proteins (p15, p16, p21 and p27). The involvement of Cdk inhibitors in carcinogenesis has been demonstrated by the studies of p16. p53 is frequently mutated in thyroid carcinomas and p21/Waf1 is a downstream effector of p53. It is conceivable that genetic defects of genes downstream in the p53 pathway could also be oncogenic. We, therefore, examined a series of 57 thyroid tumour specimens (eight follicular adenomas and 49 carcinomas) for deletion and point mutation of the p21/Waf1 gene. Three different kinds of deletions ranging from 349 to 450 bp were detected in five papillary carcinoma specimens by reverse transcription-polymerase chain reaction (RT-PCR). All the deletions were involved in the second exon of the p21/Waf1 gene. RT-PCR single strand conformational polymorphism (SSCP) analysis of remaining samples failed to reveal any point mutations in the coding region of the gene, except for a polymorphism at codon 31 (Ser to Arg). Genomic Southern blot analysis did not demonstrate any gene deletion or rearrangement in these samples, indicating abnormal RNA splicing may be involved. Analysis of intron-exon boundary and the coding region of the second exon did not reveal any mutation except for a point mutation (C to G) located 16 bp downstream from the splice donor site of the second intron in three out of five samples with p21/Waf1 deletions. Whether the mutation plays any role in aberrant RNA splicing remains to be determined. Among the five samples with p21/Waf1 gene deletions, none of them simultaneously carried a p53 or retinoblastoma (Rb) gene mutation. No p21/Waf1 abnormality was found in the benign adenomas. Thus, 12.5% (5/40) of thyroid papillary carcinoma specimens harboured p21/Waf1 gene deletions. Our data suggest that p21/Waf1 gene deletion is involved in thyroid carcinogenesis and may play an important role in thyroid cell transformation.
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PMID:Evidence of gene deletion of p21 (WAF1/CIP1), a cyclin-dependent protein kinase inhibitor, in thyroid carcinomas. 891 26

India has one of the world's highest incidences of oral cancer. It is believed that the widespread habit of betel quid chewing is an important risk factor as it exposes the oral mucosa to known carcinogens. It also induces physical abrasions, which may create mitogenic environments during wound healing as gateways for infections. A recent study from our laboratories identified human papillomavirus (HPV) DNA, mostly of the high-risk types HPV-16 and HPV-18, in 67 of 91 oral cancer lesions from a cohort of Indian patients consisting mostly of betel quid users. This suggested a viral etiology of some lesions but tumorigenesis in the absence of viruses in other lesions. Here, we examined whether the p53 gene, whose function is abrogated by the product of the HPV gene E6, would be mutated in those oral cancers that were free of HPV DNA, and we found point mutations at known hot spots for mutational alteration of p53 in 4 of 23 lesions. We also considered the possibility that p21, a target of regulation by the p53 protein, may be mutationally altered in tumors with a functional p53 gene. While we did not identify mutations in the p21 gene, 6 of 11 lesions contained a polymorphism that may be associated with cancer. Interestingly, 3 of 23 lesions had mutations in the p16 gene, a third regulator of the cell cycle which is frequently mutated in melanoma but rarely in other cancers, with 1 lesion even having a mutation in the p53 as well as in the p16 gene. Our data point to p53 and p16 as gene targets of oral carcinogenesis, with chemicals in the betel quid possibly functioning in these tumors as carcinogens.
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PMID:Mutations and polymorphisms in the p53, p21 and p16 genes in oral carcinomas of Indian betel quid chewers. 894 9

The p53-regulated gene product p21 (sdi1,cip1,waf1) negatively regulates cell growth and has been suggested to be a potential tumour-suppressor gene. To determine the sites and types of mutations which inactivate the growth-arresting activity in sdi1 cDNA, plasmids containing sdi1 cDNA and the neomycin-resistant gene were irradiated with UV light and transfected into CHO cells. The UV irradiation increased number of the geneticin-resistant colonies which should have the UV-mutated sdi1 cDNA. Sdi1 mRNA was expressed in 23 out of 36 colonies (64%). In 13 sdi1 cDNA sequences analysed, mutations were found at codon 46 in nine cDNAs, and one each at codons 34, 54, 66 and 73. All the mutation sites are in the CDK-binding region. Ten mutations (77%) (codons 46 and 66) are C to T transition mutation at the dipyrimidine sequences, which is the major type of the UV-induced mutation.
Carcinogenesis 1996 Nov
PMID:Sites and types of UV-induced mutations leading to inactivation of the growth-arresting activity in p21 (sdi1/cip1/waf1) cDNA. 896 47

In vitro cell transformation is a valuable approach for studying the mechanisms of multistep carcinogenesis of human cells. Since immortalization is an essential step for in vitro neoplastic transformation of human cells, this study addresses the question of whether mutant p53 contributes to the immortalization process of human cells. The mutant p53 gene (mp53: codon273Arg-His) was introduced into normal human fibroblasts (OUMS-24 line) and a G418-resistant clone, OUMS-24/P6 line, was obtained. This clone showed an extended life span and chromosome abnormalities, but senesced at the 79th population doubling level (PDL). When these cells were subjected to intermittent X-ray treatment, they became an immortalized cell line (OUMS-24/P6X). Although these immortalized cells showed chromosome abnormalities, they were not tumorigenic. On the other hand, normal OUMS-24 cells into which mp53 had not been introduced were not immortalized by the same X-ray treatment. These results indicate that introduction and expression of mp53 alone were not sufficient for immortalization of human cells, and that mutations of the remaining wild-type p53 or other genes may have been necessary for immortalization. In fact, no expression of the wild-type p53 was detected in the immortalized cells by RT-PCR. Expression of p21, which is located downstream of p53, was remarkably reduced in the immortalized cells, resulting in an increase in cdk2 and cdc2 kinase activity. These findings indicate that the p53-p21 cascade may play some role in the immortalization of human cells. On the other hand, there was no significant difference in expression of proteins such as Rb, p16, cdk4, cdk6, cyclin A and cyclin D1 between the normal and immortalized human fibroblasts.
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PMID:Transformation of normal human fibroblasts into immortalized cells with the mutant p53 gene and X-rays. 898 2

The platelet-activating factor PAF (1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine) is a potent lipid first messenger active in general cell activation, fertilization, inflammatory and allergic reactions, asthma, HIV pathogenesis, carcinogenesis, and apoptosis. There is substantial evidence that PAF is involved in intracellular signalling, but the pathways are poorly understood. Inactivation of PAF is carried out by specific intra- and extracellular acetylhydrolases (PAF-AHs), a subfamily of phospholipases A2 that remove the sn-2 acetyl group. Mammalian brain contains at least three intracellular isoforms, of which PAF-AH(Ib) is the best characterized. This isoform contains a heterodimer of two homologous catalytic subunits alpha1 and alpha2, each of relative molecular mass 26K, and a non-catalytic 45K beta-subunit, a homologue of the beta-subunit of trimeric G proteins. We now report the crystal structure of the bovine alpha1 subunit of PAF-AH(Ib) at 1.7 A resolution in complex with a reaction product, acetate. The tertiary fold of this protein is closely reminiscent of that found in p21(ras) and other GTPases. The active site is made up of a trypsin-like triad of Ser 47, His 195 and Asp 192. Thus, the intact PAF-AH(Ib) molecule is an unusual G-protein-like (alpha1/alpha2)beta trimer.
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PMID:Brain acetylhydrolase that inactivates platelet-activating factor is a G-protein-like trimer. 898 54

Although epidemiological and experimental studies have indicated a strong relationship between types and amount of dietary fat and colon tumorigenesis, the modulating effects of these nutritional factors at the molecular level have not been fully elucidated. Transforming proteins encoded by activated ras genes have been implicated in the etiology of many human malignancies, including colon cancer. It is now well established that the transforming ability of ras-p21 critically depends on its correct localization in plasma membrane. The posttranslational processing of the cytosolic precursor (pro-ras), as it is synthesized in the cytoplasm, and its proper anchorage to the cytoplasmic face of plasma membrane are determined by an important intermediate metabolite of dietary fat and an enzyme system that includes farnesyl protein transferase. To provide an understanding of the molecular basis of the relationship between the types and amount of dietary fat and the transforming function of ras, especially during the stages of promotion and progression of colon tumor development, we investigated the effect of various types and amount of dietary fat on the expression of ras-p21 during azoxymethane (AOM)-induced colon carcinogenesis. Male F344 rats were fed the semipurified American Institute of Nutrition-76A diet containing low-fat corn oil and were given s.c. injections of AOM dissolved in normal saline at a dose rate of 15 mg/kg body weight, once weekly, for 2 weeks. Control animals received s.c. injections of equal volumes of normal saline. Beginning 1 day after the second AOM or saline injection, groups of animals intended for the treatment with different types of high-fat dietary regimens were fed the semipurified American Institute of Nutrition-76A diets containing high levels of high-fat corn oil (HFCO) rich in omega-6 fatty acids or high levels of high-fat fish oil (HFFO) rich in omega-3 fatty acids; the remaining animals in experimental and control groups were continued on the low-fat corn oil diet until termination of the experiment. Groups of animals were sacrificed 1, 12, or 36 weeks after the last AOM or saline injection, and their colonic mucosa and grossly visible colon tumors from rats sacrificed 36 weeks after the last AOM injection were analyzed for the levels of expression of ras-p21. We found that AOM induced increasingly higher levels of ras-p21 expression with advancing stages of colon tumor development. The HFCO diet resulted in enhanced expression of AOM-induced ras-p21 as observed 36 weeks after the last AOM injection. In contrast, feeding the HFFO diet inhibited AOM-induced ras-p21 expression. These results correlate with increased incidence and multiplicity of grossly visible colon tumors in AOM-treated animals fed a HFCO diet versus decreased incidence and lower multiplicity of colon tumors in their counterparts on the HFFO diet. Further analysis of ras-p21 levels in cytosol and plasma membrane revealed that feeding a HFFO diet resulted in increasing accumulation of ras-p21 in cytoplasm with a concomitant decrease in membrane-bound ras-p21 levels as observed in animals sacrificed 12 and 36 weeks after the last AOM injection. Thus, the dietary HFCO may promote colon tumorigenesis by increasing ras-p21 expression, whereas HFFO appears to exert its antitumor activity by interfering with posttranslational modification and membrane localization of ras-p21.
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PMID:Dietary fat and colon cancer: modulating effect of types and amount of dietary fat on ras-p21 function during promotion and progression stages of colon cancer. 900 May 64


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