Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

An increased number of interphasic nucleolar organizer regions containing ribosomal cistrons associated with argyrophilic proteins (AgNORs) has been described in human malignant tumor cells. In this study variations in AgNOR numbers have been compared with changes of cell kinetics, evaluated by the mitotic count (MC) and bromodeoxyuridine labeling index (BrdU LI), during gastric carcinogenesis induced with N-methyl-N'-nitro-N-nitrosoguanidine (NG) in rats. Significant differences (2 P < 0.005) in AgNOR mean numbers, evaluated in the antral isthmic cells, in MC mean values and BrdU LI, evaluated in the whole antral cellular population, were found when comparing areas of acute gastritis, atrophy and hyperplasia in NG-treated rats with the normal mucosa in controls. No differences were observed in MC and BrdU LI between normal antrum and carcinoma cells which showed an AgNORs mean number lower than in the isthmic cells of controls (2 P < 0.005). Moreover, significant correlations were found comparing changes in AgNOR numbers with MC (r = 0.89, P < 0.001) and BrdU LI (r = 0.66, P < 0.001) in different lesions. These data show that evaluation of AgNOR numbers does not allow the identification of malignant cells in NG-induced gastric carcinoma. However AgNOR quantification seems to be a reliable index of cell kinetics and related well with the cellular dividing fraction.
Virchows Arch B Cell Pathol Incl Mol Pathol 1992
PMID:Interphasic nucleolar organizer regions expression and cell kinetics evaluation during gastric carcinogenesis induced by nitrosoguanidine in the rat. 135 3

Increased expression of multidrug-resistance (mdr) gene transcripts and of the encoded protein, P-glycoprotein, is found in many types of tumors. The biological significance of mdr overexpression during the stepwise process of neoplastic development, however, is not well understood. To assess the possible significance of mdr overexpression in carcinogenesis, we examined the cellular distributions of both mdr gene transcripts and P-glycoprotein during hepatocarcinogenesis induced in rats by the Solt-Farber protocol and then compared them to the distributions of the placental form of glutathione S-transferase (GST-P), a known marker of preneoplastic and neoplastic lesions in the liver. In situ hybridization and immunohistochemical techniques were employed. Neither mdr transcripts nor P-glycoprotein was expressed in oval cells that appeared early in the carcinogenic process. GST-P was strongly expressed in the early focal lesions, whereas the levels of mdr transcripts and P-glycoprotein expressed were low and heterogeneous. Expression of mdr transcripts and P-glycoprotein was increased and became more uniform in hyperplastic nodules and carcinomas, although considerable heterogeneity of expression was still found, particularly at the nodular stage. These data suggest that increased expression of mdr is associated with later stages of neoplastic development in the liver. Furthermore, that no chemical treatment of the animals was employed when the expression of mdr was increasing in the preneoplastic and neoplastic lesions suggests that the enhanced mdr expression is intrinsic to the carcinogenic process.
Mol Carcinog 1992
PMID:Cellular pattern of multidrug-resistance gene expression during chemical hepatocarcinogenesis in the rat. 135 97

The influence of estrogen on mammary carcinogenesis was studied in female Sprague-Dawley rats ovariectomized at the age of 36 days and given injections of 17 beta-estradiol (group I:0, II:1, III:10, IV:100, V:1000 micrograms/2 days) between the ages of 36 and 250 days and a single oral dose of 20 mg of 7,12-dimethylbenz(a)anthracene (DMBA) at the age of 50 days. No palpable mammary carcinomas were detected up to the age of 135 days. At the age of 135 days, each group was divided into two subgroups (a and b). Rats of the second subgroup (Ib, IIb, IIIb, IVb and Vb) were given additional injections of progesterone (P; 4 mg/2 days) between the ages of 135 and 250 days. At the age of 250 days, the incidence of mammary carcinoma was significantly higher in rats from group IIIb than in groups Ib and IIIa, and that in group IVa was also higher than in group Ia. The incidence in group IVb was significantly lower than in group IVa. The carcinomas in group IIIb were palpable papillo-tubular adenocarcinomas and those in group IVa were secretory micro-adenocarcinomas. These results indicate that the induction of mammary carcinomas by DMBA is totally inhibited by ovariectomy and/or high doses of estrogen, but that mammary carcinomas are initiated by DMBA under hormonal conditions in which suitable levels of estrogen are present. They also suggest that the growth of DMBA-induced mammary carcinomas in the rats from group III were accelerated by additional injections of P and that those in rats from group IV were inhibited by additional P.(ABSTRACT TRUNCATED AT 250 WORDS)
Virchows Arch B Cell Pathol Incl Mol Pathol 1992
PMID:Influence of estrogen and progesterone on the induction of mammary carcinomas by 7,12-dimethylbenz(a)anthracene in ovariectomized rats. 136 Jul 23

We previously reported a separation, on an organomercurial column, of transcriptionally inactive nucleosomes (class 1) from those containing active gene sequences (classes 2 and 3). In this paper, we analyzed nucleosomal damage caused by exposure of HeLa S3 cells in suspension culture to the directly alkylating carcinogen N-methyl-N-nitrosourea (MNU). The extent and site of methylation induced by the compound in nucleosomal DNA and RNA were determined by cell incubation in the presence of [3H]MNU. The highest amount of damage was detected in DNA of class 3 nucleosomes, while RNA alkylation was comparable in all nucleosomal classes. Cellular capacity for repair of MNU-induced DNA strand breaks (estimated after a short pulse with [3H]thymidine) was found to be higher in active nucleosomal fractions (classes 2 and 3) than in the inactive fraction (class 1). Our data support the postulate that chromatin primary structure plays a role in modulating carcinogen damage to chromosomal macromolecules and in DNA strand breakage and repair mechanisms. Some of these initial steps are believed to be critical in the process of carcinogenesis.
Mol Carcinog 1992
PMID:Effects of N-methyl-N-nitrosourea on transcriptionally active and inactive nucleosomes: macromolecular damage and DNA repair. 137 28

Acyltransferase-mediated mutagenic and metabolic activation of N-acetoxy-4-acetylaminobiphenyl (N-OAc-AABP) by hepatic tissues of rats and dogs were compared. N-OAc-AABP was mutagenic in Salmonella typhimurium TA98 even in the absence of exogenous enzyme(s). However, supplementation with hepatic microsomes from dogs showed a dose-dependent increase in mutagenicity of N-OAc-AABP, whereas under the same conditions, rat microsomes were inactive. Incubation of liver microsomes with RNA showed that 46.4 and 11.2 nmole of [3H]N-OAc-AABP were bound/mg RNA/mg protein with dogs and rats, respectively. The hepatic microsome-mediated binding and mutagenicities of N-OAc-AABP were blocked by paraoxon, suggesting the involvement of deacetylase(s) in the activation process. Analyses of the in vitro incubates of N-OAc-AABP with rat and dog liver microsomes revealed the O-deacetylation product N-hydroxy-4-acetylaminobiphenyl (N-OH-AABP) as the major metabolite. The ratios of O-deacetylation of N-O[14C]Ac-AABP versus N-deacetylation of N-OAc-[14C]AABP for hepatic microsomes from dogs and rats were 2.9 and 7.2, respectively. The O- and N-deacetylases are also distributed in bladder tissues and their activities in comparison to the hepatic tissues were lower and amounted to 14.2 and 5.0 nmoles (O/N-deacetylation ratio 2.8) for dogs and 14.8 and 1.7 nmoles per mg protein per min (O/N-ratio of 8.7) for rats. The microsomes from bladder tissues also catalyzed the binding of [3H]N-OAc-AABP to RNA and enhanced its mutagenic response in TA98, both of which were blocked by paraoxon. The occurrence of deacetylase(s) in the target tissues of the bladder carcinogen 4-acetylaminobiphenyl (AABP) suggests that metabolic activation of some of the proximate metabolites could occur within these target organs. Furthermore, since the O-deacetylation product N-OH-AABP is relatively innocuous compared to the N-deacetylation product N-acetoxy-4-aminobiphenyl, these results imply that the refractiveness of rats for 4-aminobiphenyl or AABP-induced bladder carcinogenesis might in part be associated with the higher ratios of microsomal O/N-deacetylase activities. Thus susceptibility to arylamine or arylacetamide-induced liver and bladder carcinogenesis might be influenced by the microsomal deacetylases.
Environ Mol Mutagen 1992
PMID:Comparison of acyltransferase-mediated mutagenicity and nucleic acid binding of N-acetoxy-4-acetylaminobiphenyl by hepatic and bladder microsomes from rats and dogs. 137 79

In normal epidermis, the expression of keratins 1 and 10 is associated with the loss of proliferative capacity and the onset of terminal differentiation. Keratins 1 (K1) and 10 (K10) are commonly expressed in the differentiating layer of benign tumors, but are lost during progression from the benign to the malignant state in skin carcinogenesis. Active gene constructs of mouse K1 and K10 were introduced into papilloma and carcinoma cell lines derived from keratinocytes to analyze the consequences of the expression of these keratins on the organization of the endogenous cytoskeletal network and on the mitotic activity of the recipient cells. Exogenous K1 integrated into the preexisting keratin K5/K14 network of both SLC-1 carcinoma and 308 papilloma cells. The formation of a recombinant cytoskeleton was more restricted for K10 than for K1 and appeared to be related to a requirement for cessation of cell division before K10 could integrate. The integration of exogenous K1 filaments into the endogenous keratin network was compatible with sustained proliferation of SLC-1 carcinoma cells in vitro. However, the exogenous gene was not expressed in tumor grafts in vivo. In contrast, stable K1 or K10 transfectants could not be selected in 308 cells, suggesting that benign tumor cells expressing suprabasal keratins cannot sustain proliferation.
Mol Carcinog 1992
PMID:Relationship between the expression of differentiation-specific keratins 1 and 10 and cell proliferation in epidermal tumors. 138 Feb 47

Keratins have been demonstrated to be suitable markers of changes taking place during epithelial neoplasia. Therefore, we analyzed 18 mouse skin tumors (nine papillomas and nine squamous cell carcinomas), induced either by two-stage carcinogenesis with 7,12-dimethylbenz[a]anthracene(DMBA)/12-O-tetradecanoylphorbol-13-acetat e or complete carcinogenesis with DMBA, by immunofluorescence with a monoclonal antibody to keratin (K) 8 (TROMA-1). Immunoperoxidase staining and immunoblotting were also used on selected tumor samples to further explore for the presence of K8. All of the papillomas tested were negative for the presence of K8, whereas the carcinomas were positive. The level of K8 expression in carcinomas showed a positive correlation with the degree of malignancy. Northern blot analysis using a K8 cDNA probe suggested that control of K8 expression in mouse skin tumors occurs at the transcriptional level. Double-label immunofluorescence staining using TROMA-1 and RK13 antibodies demonstrated that K8 did not generally colocalize with K13, a keratin normally found in internal stratified epithelial but aberrantly expressed in mouse epidermal tumors. Furthermore, tumors expressing high levels of K8 showed a reduced expression of K13. Histological examination of immunoperoxidase-stained tumors demonstrated that K8-positive cells were mainly found in anaplastic areas, whereas K13 foci were restricted to well-differentiated regions. Our results demonstrate that K8 expression is a marker of late stages of carcinoma progression in the mouse skin carcinogenesis model.
Mol Carcinog 1992
PMID:Aberrant expression of the simple epithelial type II keratin 8 by mouse skin carcinomas but not papillomas. 138 41

In human lung cancers, alterations of both a dominant oncogene (ras) and a tumor suppressor gene (p53) have been identified. Polymerase chain reaction (PCR) analysis of mRNA was used to amplify the c-Ki-ras-2 and p53 genes from Syrian golden hamsters. The PCR products were confirmed by predicted-size analysis, probing with nonradioactive (biotin-labeled) oligonucleotides, and direct sequencing. Lung tumors were produced in hamsters by repeated injections of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). Of six tumors examined, three (50%) had mutations in codon 12 of Ki-ras. Examination of the conserved regions of p53 revealed no mutations. We conclude that NNK-induced carcinogenesis in the hamster results in characteristic alterations of Ki-ras but may not necessarily involve the p53 gene.
Mol Carcinog 1992
PMID:Mutational analysis of a dominant oncogene (c-Ki-ras-2) and a tumor suppressor gene (p53) in hamster lung tumorigenesis. 144 20

The presence of an activating mutation in the Ha-ras gene in hamster cheek pouch tumors induced by 7,12-dimethylbenz[a]anthracene (DMBA) complete carcinogenesis was investigated. The normal sequence of a fragment of genomic DNA encompassing codon 61 of the Ha-ras gene was amplified by the polymerase chain reaction using primers designed for a highly conserved region of the mouse Ha-ras-1 gene. The sequence of the amplified fragment was determined by a direct sequencing technique and exhibited 83.3% and 87.5% homology with the corresponding human and mouse sequences, respectively. At the amino acid level, the sequence was identical among the three species. Paraffin sections of 11 squamous cell carcinomas of the cheek pouch were used to detect mutated Ha-ras alleles. DNA sequencing of the tumors showed that six of 11 tumors presented an A----T transversion in the second position of codon 61, resulting in an amino acid change from glycine to leucine. As has been demonstrated in other systems, we have shown a specific mutation of the Ha-ras gene in chemically induced tumors of the hamster cheek pouch, further supporting the role of this oncogene in chemical carcinogenesis.
Mol Carcinog 1992
PMID:Activating mutation of the Ha-ras gene in chemically induced tumors of the hamster cheek pouch. 149 2

As part of an evaluation of the effectiveness of using ras mutation analysis for distinguishing carcinogen-induced from spontaneous tumors, we examined the profile of ras gene point mutations in spontaneous, 7,12-dimethylbenz[a]anthracene (DMBA)-induced, and N-nitrosodiethylamine (DEN)-induced lung tumors from Crl:CD-1(ICR)BR (CD-1) mice. Although all of the lung tumors were assayed for mutations in the Ha-ras, Ki-ras, and N-ras genes (codons 12, 13, and 61), only Ki-ras mutations were found, which is consistent with other studies that have noted a strong preference for Ki-ras gene activation in mouse, rat, and human lung tumors. We found that spontaneous CD-1 mouse lung tumors had a very high frequency of Ki-ras gene activation (17 of 20 tumors; 85%), distributed among codons 12 (5 of 20), 13 (1 of 20), and 61 (11 of 20). DMBA-induced lung tumors had a slightly higher frequency of Ki-ras gene mutations (16 of 16; 100%), again distributed among codons 12 (5 of 16), 13 (2 of 16), and 61 (9 of 16). However, seven of the DMBA tumors had mutations qualitatively different from those found in spontaneous tumors. In contrast to DMBA-induced tumors, DEN-induced tumors had a lower frequency of Ki-ras mutations (36%) when compared with spontaneous lung tumors, suggesting that DEN primarily induces lung carcinogenesis by a mechanism other than ras gene activation. Thus, although spontaneous and induced CD-1 mouse lung tumors have a strong tissue-specific preference for carrying an activated Ki-ras gene, the nature of the initiating carcinogen can influence the frequency or profile of Ki-ras mutations.
Mol Carcinog 1992
PMID:Activation of the Ki-ras gene in spontaneous and chemically induced lung tumors in CD-1 mice. 150 45


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