Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.3.44 (P-glycoprotein)
 13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Overexpression of the MDR1 product, P-glycoprotein (Pgp), has been shown to be one of the mechanisms underlying the development of multidrug resistance (MDR). Recently, one mutant p53 has been shown to stimulate the MDR1 gene promoter in vitro, whereas wild-type p53 repressed this activity. We measured Pgp and p53 expression by immunoblotting in 34 colorectal tumours, and performed mutation analyses on the p53-positive tumours to confirm the presence of mutant p53 protein. Tumour DNA indices (DIs) were also measured using flow cytometry. Pgp was detected in 44% (15/34) of the tumours and in 100% (13/13) of the normal mucosas (P = 0.0005), with highest levels of expression seen in normal mucosa, suggesting that initial drug resistance in colorectal tumours is not caused by Pgp. Highly DNA aneuploid tumours demonstrated the lowest levels of Pgp expression relative to moderately aneuploid and diploid colorectal tumours. p53 protein was detected in 53% (18/34) of the tumours, and 12 of 14 p53-positive tumours had p53 gene mutations, p53-negative tumours had approximately twice the level of Pgp expression of p53-positive tumours. Pgp expression was not associated with either p53 expression (P = 0.73) or incidence of p53 gene mutation (P = 0.70), suggesting that mutant p53 does not induce Pgp overexpression in colorectal carcinomas.
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PMID:P-glycoprotein is not expressed in a majority of colorectal carcinomas and is not regulated by mutant p53 in vivo. 764 Feb 10

Approximately 30-50% of cases of ovarian adenocarcinoma harbour mutations in the p53 tumour-suppressor gene associated with elevated levels of the protein detected by immunohistochemical staining. To investigate any relation between the presence of mutant p53 and clinicopathological features of disease, we examined a series of 50 cases of epithelial ovarian adenocarcinoma for expression of p53 by immunohistological staining on fixed, paraffin-embedded tissue sections using the polyclonal antibody CM1, and by direct nucleotide sequencing of polymerase chain reaction-amplified DNA from selected cases. Of the 50 cases examined, 28 (56%) were p53 positive and there was no significant correlation between p53 status and differentiation stage, clinical (FIGO) stage, multidrug resistance (mdr-1 P-glycoprotein) expression or response to treatment. However, we observed a statistically significant difference between the high prevalence of p53-positive serous tumours (18 out of 23) and the lower prevalence of p53-positive cases in mucinous tumours (3 of 12) suggesting that factors related to disease aetiology, associated with these histological subtypes, may determine the prevalence of functional inactivation of the p53 tumour-suppressor gene in ovarian adenocarcinoma.
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PMID:Immunohistochemical detection of mutant p53 protein in epithelial ovarian cancer using polyclonal antibody CMI: correlation with histopathology and clinical features. 812 98

The overexpression of P-glycoprotein is thought to be responsible for resistance to chemotherapy in some non-responsive cancers. The mechanism by which P-glycoprotein is overexpressed in human tumors is poorly understood. However, several lines of evidence suggest that the major regulatory mechanism of P-glycoprotein overexpression in human tumors is at the transcriptional level. During tumor progression one of the most commonly observed alterations is mutation of the p53 tumor-suppressor gene. It has been shown that the p53 protein plays a role in transcriptional regulation. To gain insight into the effect p53 protein may have on P-glycoprotein promoter activity, we transiently co-transfected plasmids containing the hamster pgp1 or human mdr1 promoter linked to the chloramphenicol acetyltransferase (CAT) reporter gene with plasmids encoding either wild-type or mutant p53 protein into Chinese hamster ovary (CHO) cells. In this report, we show that wild-type p53 protein represses P-glycoprotein promoter activity, while mutant forms of p53 protein enhance P-glycoprotein promoter activity. Furthermore, we present data which indicate that the transcriptional regulatory effects of p53 are mediated through interactions with pgp1/mdr1 core promoter sequences. These findings have implications for our understanding of the molecular mechanism(s) by which p53 protein functions as a transcriptional regulator of gene expression. In addition, our results suggest a mechanism by which P-glycoprotein may be overexpressed in human cancers that also express mutant forms of p53 protein.
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PMID:The core promoter region of the P-glycoprotein gene is sufficient to confer differential responsiveness to wild-type and mutant p53. 850 78

The ability of ras oncogenes and mutant p53 to activate reporter gene expression from human and rodent mdr1 gene promoters was described, although functional significance of this finding was unclear. We analyzed the influence of various forms of recombinant human ras and p53 on the mdr1 gene expression and P-glycoprotein (Pgp) function in rodent immortalized fibroblasts. The ras genes, in addition to activation of exogenous human mdr1 gene promoter, caused an increase in (i) expression of endogenous mdr1 mRNA, (ii) Pgp activity as determined by flow cytometry analysis of Rhodamine 123 exclusion, and (iii) resistance of cells to the cytotoxic action of colchicine and some other drugs. To elucidate whether the same signalling pathway is responsible for multidrug resistance induced by various oncogenes and protein kinase C (PKC), we tested the effects of v-mos and the PKC agonist 12-O-tetradecanoylphorbol-13-acetate. Similarly to cells transformed by ras, a Rat1 subline transformed by the v-mos oncogene was characterized by decreased drug sensitivity. On the contrary, Rat1 cells treated with the protein kinase C agonist 12-O-tetradecanoylphorbol-13-acetate showed neither increased mdr1 mRNA expression nor stimulation of Pgp function. Introduction by retrovirus-mediated gene transfer of wild-type p53 into Rat1 cells or into murine p53-deficient 10(1) and 10(3) cells did not change the Pgp function significantly, whereas in Rat1 cells transformed by activated N-ras or v-mos, expression of wild-type p53 caused partial reversion of oncogene-induced drug resistance.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Influence of exogenous ras and p53 on P-glycoprotein function in immortalized rodent fibroblasts. 852 64

Expression of both P-glycoprotein (P-gp) and mutant p53 have recently been reported to be associated with poor prognosis of breast cancer. The expression of P-gp is associated in vitro and in vivo with cross-resistance to several anti-cancer drugs. p53 plays a regulatory role in apoptosis, and mutant p53 has been suggested to be involved in drug resistance. Interestingly, in vitro experiments have shown that mutant p53 can activate the promoter of the MDR1 gene, which encodes P-gp. We investigated whether p53 and P-gp are simultaneously expressed in primary breast cancer cells and analysed the impact of the co-expression on patients prognosis. Immunohistochemistry was used to investigate P-gp expression (JSB-1, C219) and nuclear p53 accumulation (DO-7) in 20 operable chemotherapy untreated and 30 locally advanced breast cancers undergoing neoadjuvant chemotherapy with doxorubicin and cyclophosphamide. Double immunostaining showed that P-gp expression and nuclear p53 accumulation often occur concomitantly in the same tumour cells. A correlation between p53 and P-gp expression was found in all 50 breast cancers (P = 0.003; Fisher's exact test). P-gp expression, nuclear p53 accumulation, and co-expression of p53 and P-gp were more frequently observed in locally advanced breast cancers than in operable breast cancers (P = 0.0004, P = 0.048; P = 0.002 respectively. Fisher's exact test). Co-expression of p53 and P-gp was the strongest prognostic factor for shorter survival by multivariate analysis (P = 0.004) in the group of locally advanced breast cancers (univariate analysis: P = 0.0007). Only 3 out of 13 samples sequentially taken before and after chemotherapy displayed a change in P-gp or p53 staining. In conclusion, nuclear p53 accumulation is often associated with P-gp expression in primary breast cancer, and simultaneous expression of p53 and P-gp is associated with shorter survival in locally advanced breast cancer patients. Co-expression of P-gp and mutant p53 belong to a series of molecular events resulting in a more aggressive phenotype, drug resistance and poor prognosis.
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PMID:p53 and P-glycoprotein are often co-expressed and are associated with poor prognosis in breast cancer. 867 60

Chemotherapeutic drug resistance is a major clinical problem and cause for failure in the therapy of human cancer. One of the goals of molecular oncology is to identify the underlying mechanisms, with the hope that more effective therapies can be developed. Several mechanisms have been suggested to contribute to chemoresistance: 1) amplification or overexpression of the P-glycoprotein family of membrane transporters (eg, MDR1, MRP, LRP) which decrease the intracellular accumulation of chemotherapy; 2) changes in cellular proteins involved in detoxification (eg, glutathione S-transferase pi, metallothioneins, human MutT homologue, bleomycin hydrolase, dihydrofolate reductase) or activation of the chemotherapeutic drugs (DT-diaphorase, nicotinamide adenine dinucleotide phosphate:cytochrome P-450 reductase); 3) changes in molecules involved in DNA repair (eg, O6-methylguanine-DNA methyltransferase, DNA topoisomerase II, hMLH1, p21WAF1/CIP1; 4) activation of oncogenes such as Her-2/neu, bcl-2, bcl-XL, c-myc, ras, c-jun, c-fos, MDM2, p210 BCR-abl, or mutant p53. An overview of these resistance mechanisms is presented, with a particular focus on the role of oncogenes. Some current strategies attempting to reverse their effects are discussed.
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PMID:Role of oncogenes in resistance and killing by cancer therapeutic agents. 909 Apr 98

A role for p53 in the regulation of multidrug-resistance (MDR) has been postulated as wild-type p53 suppresses and mutant p53 specifically activates the mdr1 promoter. Moreover, changes in p53 expression and/or functions could be implicated in drug resistance. As the parental lymphoblastic CCRF-CEM cell line has been described as expressing a mutated form of p53, we have examined p53 and mdm2 protein levels in the human multidrug-resistant CEM-VLB cell line variant. These drug-resistant CEM-VLB cells, which have increased expressions of mdr1 and P-glycoprotein, displayed p53 and mdm2 protein expressions similar to those observed in their sensitive CCRF-CEM counterparts. Treatment of these drug-resistant cells with non-toxic doses of the resistance-inducing drug vinblastin induced a strong increase in p53 protein and mRNA but was ineffective on mdm2 protein expression, or mdr1 mRNA expression. These data indicate that mutant p53 protein was not overexpressed in these MDR cells. This overexpression could be induced by microtubule-active drug treatment, but, as previously observed in other sensitive cell lines, mutant p53 from these MDR cells was unable to positively regulate mdm2 gene product expression.
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PMID:P53 protein expression in human multidrug-resistant CEM lymphoblasts. 911 32

Recently reported morphologic and molecular genetic evidence suggests that some ovarian carcinomas arise from their benign and low malignant potential (LMP) counterparts. In order to help reach a better understanding of ovarian tumorigenesis, we studied a wide range of gene products involved in cellular growth regulation in archival material obtained from three groups of tumors with graduated malignant potential. Immunohistochemical staining was performed for Ki-67, proliferating cell nuclear antigen (PCNA), epidermal growth factor receptor (EGFR), HER-2/neu-encoded receptor protein, p53 gene product, and multidrug resistance gene product (P-glycoprotein). The expression of EGFR, HER-2/neu-encoded receptor protein, and mutant p53 product was significantly lower in LMP tumors than in carcinomas (p < 0.05). HER-2/neu immunopositivity was more prevalent in adenocarcinomas than in LMP tumors, and the proportion of HER-2/neu-positive adenocarcinomas increased with the progression of the disease. The staining differences between LMP tumors and adenocarcinomas with antibodies against Ki-67, PCNA, and P-glycoprotein were not statistically significant. Immunohistochemical detection of EGFR, HER-2/neu, and p53 in ovarian epithelial tumor is relevant to ovarian tumorigenesis. It could serve as a powerful tool for the pursuit of retrospective studies focused on these important biologic markers.
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PMID:Immunohistochemical assessment of proliferation markers and altered gene expression in archival specimens of ovarian epithelial tumors. 939 93

To identify prognostic factors alternative or additional to P-glycoprotein (Pgp), we studied the impact of the multidrug resistance-related protein (MRP), bcl-2 (flow cytometry), mutant p53 (single-strand conformation polymorphism), and heat-shock protein 27 (HSP27, Western blotting) in myeloid blasts obtained at the time of diagnosis in patients with de novo acute myeloid leukemia (AML). We collected bone marrow samples from untreated AML patients, prepared the cells as well as the cellular protein, and froze all the material. We then analyzed 20 patients who responded with complete remission (CR) and 20 patients who had blast persistence (BP). The purpose of the study was to determine whether leukemic blasts from patients with BP were more resistant to chemotherapy than those from patients with CR. There was no significant correlation between the expression of any of these proteins alone and treatment outcome in both groups studied. In contrast, there was a significant correlation between the coexpression of at least two of these proteins and response (p = 0.0298), which turned out to be a significant independent prognostic factor for treatment failure (p = 0.0329, relative risk = 1.5) according to multivariate analysis. We conclude that drug resistance in AML is multifactorial. Thus, coexpression of different resistance mechanisms may be responsible for the primary drug resistance in de novo AML.
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PMID:In acute myeloid leukemia, coexpression of at least two proteins, including P-glycoprotein, the multidrug resistance-related protein, bcl-2, mutant p53, and heat-shock protein 27, is predictive of the response to induction chemotherapy. 980 49

We describe a patient with a metastasized adrenocortical cancer who exhibited excessive production of both glucocorticoids and mineralocorticoids combined with suppressed androgen production. Unusual steroid metabolites found in the patient's urine have not been described previously in association with this tumor type. Investigation of the multidrug resistance phenotype in single-cell suspensions of the tumor revealed low expression of multidrug resistance protein but high expression of P-glycoprotein (Pgp) and lung resistance-related protein. Functional Pgp in these tumor cells was shown by the modulatory effect of PSC833 on daunorubicin accumulation. Mitotane, at a concentration achieved in this patient's plasma, completely reversed the Pgp-related resistance both in the Pgp-overexpressing KB8-5 cell line and in the patient's tumor cells. On the basis of these in vitro results, the patient was treated with a combination of multidrug resistance drugs (doxorubicin, vincristine, and etoposide) plus mitotane as a Pgp modulator. This treatment was ineffective, however. A chemosensitivity assay demonstrated that the tumor cells were highly resistant to the drugs used. The adrenocortical cancer cells expressed mutant p53, and no evidence for induction of apoptosis by these drugs was found.
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PMID:A patient with adrenocortical carcinoma: characterization of its biological activity and drug resistance profile. 981 96


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