Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: EC:3.6.3.44 (P-glycoprotein)
13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the present paper it is shown that the marine sponges Geodia cydonium and Verongia aerophoba contain the gene coding for P-glycoprotein P170, also known as a multidrug-resistance gene. Western blot studies revealed that polyclonal antibodies raised against hamster P170 cross-react with the sponge polypeptide of Mr 125,000. After endoglycosidase F treatment, the sponge P125 is converted to a polypeptide of Mr 105,000. Northern blot studies, using the human P170 cDNA probe, revealed a size of 4.2 kb for the sponge P125 transcript. The level of this transcript does not change in response to incubation with the aggregation factor. Confocal laser scanning microscopy showed that P125 is a cell membrane bound protein. In addition, sponge membrane vesicles possess a potential to bind in vitro 2-acetylamino-fluorene, vincristine and daunomycin. This process is Verapamil-sensitive, a characteristic known also for the mammalian vesicle associated P170. The data reported demonstrate that the classical multidrug resistance mechanism, described in drug-resistant tumor cell lines, functions also in sponges and may explain the relative resistance of these animals to pollution.
Carcinogenesis 1992 Jan
PMID:Expression of P-glycoprotein gene in marine sponges. Identification and characterization of the 125 kDa drug-binding glycoprotein. 134 72

K1 is a murine monoclonal antibody (MAb) derived from a hybridoma generated by the fusion of splenocytes of BALB/c mice immunized with a human ovarian tumor cell line, OVCAR-3. This antibody reacts strongly with epithelial ovarian tumors and mesotheliomas. The antigen recognized by MAb K1, designated CAK1, has recently been characterized as a 40-kDa protein probably anchored to the cell surface by glycosyl-phosphatidylinositol. Using immunoperoxidase histochemical methods, we examined 37 squamous-cell carcinoma (SqCC) samples from cervix, lung, esophagus and other origins, and 12 normal squamous epithelia of the cervix and esophagus for their reactivity with MAb K1. Of the SqCC specimens, 81% showed K1 reactivity with variable intensity, but none of 12 normal tissue samples of squamous epithelia did so. Two patterns of CAK1 expression in tumor samples were found, i.e., a heterogeneous pattern with strong intensity, and a homogeneous pattern with weak intensity. Three carcinomas in situ of the larynx, vulva and esophagus were moderately positive with K1, suggesting that CAK1 antigen may occur in the early stage of carcinogenesis of SqCC. The expression of CAK1 was also compared with expression of CA125, HER-2/neu, p53 and P-glycoprotein, and MAb K1 was found to react most consistently with SqCC. Since K1 reacts with a majority of cervical and esophageal carcinomas but has no detectable reactivity in normal epithelia of the cervix uteri and esophagus, MAb K1 could be of value as a reagent to help distinguish between normal and neoplastic cells on sections as well as in cytological samples.
...
PMID:Frequent expression of the tumor antigen CAK1 in squamous-cell carcinomas. 135 Oct 45

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.
...
PMID:Cellular pattern of multidrug-resistance gene expression during chemical hepatocarcinogenesis in the rat. 135 97

Tumor cells exposed in tissue culture to one of several different classes of antineoplastic agents, including anthracyclines, vinca alkaloids, epipodophyllotoxins, and certain antitumor antibiotics, can develop resistance to the selecting agent and cross resistance to the other classes of agents. This phenomena of multidrug resistance is generally associated with decreased drug accumulation and overexpression of a membrane glycoprotein. This membrane protein, referred to as P-glycoprotein, apparently acts as an energy-dependent drug efflux pump. Multidrug resistance in human MCF-7 breast cancer cells selected for resistance to adriamycin (AdrR MCF-7) is associated with amplification and overexpression of the mdr1 gene which encodes P-glycoprotein. A number of other changes are also seen in this resistant cell line including alterations in Phase I and Phase II drug metabolizing enzymes. Similar biochemical changes occur in a rat model for hepatocellular carcinogenesis and are associated in that system with broad spectrum resistance to hepatotoxins. The similar changes in these two models of resistance suggests that these changes might be part of a battery of genes whose expression can be altered in response to cytotoxic stress, thus rendering the cell resistant to a wide variety of cytotoxic agents.
...
PMID:Keynote address: multidrug resistance: a pleiotropic response to cytotoxic drugs. 167 83

The most frequently reported alteration of multidrug resistance (MDR) is the overexpression of the 170 kd membrane glycoprotein. An increased expression of the MDR-gene in pre-neoplastic and neoplastic liver lesions produced experimentally by different carcinogens has been reported. As shown in rat liver by stop experiments, specific carcinogen-induced alterations can be separated from non-specific, toxic changes. Therefore, we induced rat hepatocellular carcinomas with N-nitrosomorpholine and investigated whether expression of the MDR-gene also takes place in hepatocellular carcinomas after withdrawal of the carcinogen. Using mAb C219 against P-glycoprotein, both normal liver and hepatocellular carcinomas show specific immunoreactivity by means of immunofluorescence and immunohistochemistry. In hepatocellular carcinomas, however, the reaction is increased if compared to normal liver of untreated control animals. These results were confirmed by immunoblotting. Using the cDNA probe 1.5, a significant increase in MDR-gene transcripts was found in hepatocellular carcinomas as compared to normal liver.
Carcinogenesis 1990 Jan
PMID:Overexpression of P-glycoprotein in rat hepatocellular carcinomas induced with N-nitrosomorpholine. 196 29

Glutathione S-transferases (GSTs) have been reported to be elevated in some forms of hepatic carcinogenesis, in multidrug resistant (MDR) cells exhibiting elevated P-glycoprotein, and in cells resistant to alkylating agents independent of the MDR phenotype. The reported elevation of GST in association with the MDR phenotype and the overexpression of P-glycoprotein along with induction of GST in hepatic carcinogenesis suggest a correlation in the two mechanisms of cellular detoxification. To evaluate this hypothesis we examined the expression of GSTs in an MDR Chinese hamster fibroblast cell line overexpressing P-glycoprotein. We were unable to demonstrate concordant elevation of GST in these MDR cells. We conclude that GST expression is independent of P-glycoprotein expression in MDR Chinese hamster fibroblasts. The overexpression of GSTs in certain cells may provide an alternative mechanism for the development of drug resistance, either in association with or independent of P-glycoprotein overexpression, but is not essential for the MDR phenotype.
...
PMID:Glutathione S-transferase and P-glycoprotein in multidrug resistant Chinese hamster cells. 197 11

To investigate the role of carcinogenesis in determining the response of tumors to anticancer drugs, we have used the in vivo model of multistage carcinogenesis of the mouse skin. Mice were initiated with Harvey murine sarcoma virus or single and repeated applications of dimethylbenzanthracene (DMBA). The papillomas which developed as a result of these initiation protocols were monitored quantitatively for their response to the anticancer drug doxorubicin. A single dose of 10 mg/kg doxorubicin is relatively inefficient at reducing the frequency of papillomas arising as a result of either single or repeated applications of the chemical DMBA. However, virally initiated papillomas are sensitive to the single 10-mg/kg dose of doxorubicin and are reduced in frequency by greater than 80%. Repeat treatment with four doses of 5 mg/kg doxorubicin over a 4-week period also reveals differences in the responses of the papillomas to doxorubicin. As with the single dose of doxorubicin, papillomas initiated with multiple applications of DMBA showed only a limited response to four 5-mg/kg doses of doxorubicin. In comparison both the virally initiated and the single DMBA initiated papillomas responded to the four doses of doxorubicin and are reduced in frequency by about 80%. These data show that the response of papillomas to doxorubicin is related to the initiating event. Papillomas derived by viral initiation are most sensitive to doxorubicin while increasing the level of exposure to the chemical carcinogen DMBA increases the proportion of papillomas which do not respond to treatment with doxorubicin. There was no obvious relationship between the method of initiation or the treatment of the mice with doxorubicin and the levels of P-glycoprotein expression observed in the papillomas. All the papillomas expressed detectable levels of P-glycoprotein approaching that of the multidrug resistant cell line, CHRC5.
...
PMID:Response of mouse skin tumors to doxorubicin is dependent on carcinogen exposure. 197 37

We have examined the relationship between transformation and multidrug resistance by employing the v-H-ras or v-raf oncogenes to transform rat liver epithelial (RLE) cells in vitro. The data indicate that transformation of RLE cells with v-H-ras or v-raf results in increased resistance to the cytotoxins adriamycin, vinblastine and 2-acetylaminofluorene. This multidrug resistance is accompanied by increasing expression of P-glycoprotein (MDR-1) and glutathione-S-transferase P (GST-P). Thus, neoplastic transformation of RLE cells with v-raf or v-H-ras, independently of chemical exposure, results in multidrug resistance.
Carcinogenesis 1988 Dec
PMID:Transformation of rat liver epithelial cells with v-H-ras or v-raf causes expression of MDR-1, glutathione-S-transferase-P and increased resistance to cytotoxic chemicals. 290 2

Adenomatous hyperplasia in the human liver with cirrhosis is similar to the hyperplastic nodule in rat hepato-carcinogenesis in that the mdr gene or its product P-glycoprotein is overexpressed. We immunohistochemically stained archival formalin-fixed, paraffin-embedded sections of 15 adenomatous hyperplasias with or without hepatocellular carcinoma in livers with cirrhosis, using the avidin-biotin-complex method and the JSB-1 monoclonal antibody which specifically binds the cytoplasmic epitope of P-glycoprotein. Of 15 cases with adenomatous hyperplasia, four were found solely in livers with cirrhosis. In six cases, adenomatous hyperplasia and hepatocellular carcinoma were found in the same liver separately. Hepatocellular carcinoma was discovered within adenomatous hyperplasia in five cases. All 15 livers with cirrhosis and those with adenomatous hyperplasia were positively stained for P-glycoprotein. When the grade of staining was compared between adenomatous hyperplasia and the surrounding liver, P-glycoprotein was overexpressed in 12 of 15 cases with adenomatous hyperplasia. P-glycoprotein was also stained more strongly in well-differentiated hepatocellular carcinoma than in the liver, but the staining grade of hepatocellular carcinoma was weaker than that of adenomatous hyperplasia. Moreover, the glycoprotein expression was less when the tumor was less differentiated.
...
PMID:Overexpression of P-glycoprotein in adenomatous hyperplasia of human liver with cirrhosis. 754 Jun 36

In this report the effects of single doses of ionizing radiation on the mRNA expression of several proteins involved in multiple drug resistance were analyzed. Murine NIH 3T3 cells treated with single doses of 5, 10 and 20 Gy during the time interval from 1.5 to 72 h after irradiation were compared with their corresponding controls at the same points of time. The glutathione S-transferase-pi (GST pi) level was elevated in cells treated with 10 or 20 Gy from 24 to 72 h after irradiation compared with the control. Topoisomerase II alpha and thymidylate synthase were decreased in irradiated cells 24-72 h after exposure. These down-regulations were associated with cellular proliferation, determined by mRNA expression of the proliferation marker histone 3. Irradiated cells exhibited no alteration in the P-glycoprotein or glutathione peroxidase mRNA content. The finding that GST pi mRNA was overexpressed after irradiation was validated by investigations on a human lung carcinoma cell line (LXF 289) on the mRNA and protein level. Thus, our results indicate that irradiation alters the expression of proteins involved in multidrug resistance and may, therefore, play a role in clinical drug response.
Carcinogenesis 1995 Sep
PMID:Effects of single doses of irradiation on the expression of resistance-related proteins in murine NIH 3T3 and human lung carcinoma cells. 755 53


1 2 3 4 5 6 7 Next >>

---