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 P-glycoprotein, the plasma membrane protein product of the MDR1 gene, is a major determinant in the development of resistance to a large number of cancer chemotherapeutic agents. A battery of antibodies, including the MDR1 gene-specific monoclonal antibody (mAb) C494, is used to evaluate human tissues in clinical multidrug resistance surveillance and modulation trials. In rat liver fractions, we report that mAb C494 strongly cross-reacted with a nonmembranous M(r) approximately 130,000 protein, comigrating with core-glycosylated human MDR1 on 7% sodium dodecyl sulfate-polyacrylamide gel electrophoresis. By immunoblotting and microsequence analysis, this protein was identified as pyruvate carboxylase (PC), an abundant mitochondrial enzyme. A search of the National Center for Biotechnology Information data base, using the epitope-specific sequence of mAb C494, revealed that PC (mouse) contains four of the five most reactive amino acids (TLEG), located near the COOH-terminal end of PC at positions 1167-1170. mAb C494 specifically reacted with PC purified from bovine liver; immunoreactivity was completely abolished by preincubating mAb C494 in the presence of excess synthetic C494 epitope-specific peptide. Furthermore, in cryosections of human skeletal muscle, a tissue known not to express P-glycoprotein, peptide-displaceable immunohistochemical staining with mAb C494 showed a distinct mitochondrial pattern specific to type 1 fibers. Variable immunostaining results were obtained with formaldehyde-fixed, paraffin-embedded muscle and isolated liver mitochondrial preparations. In summary, mAb C494 cross-reacted strongly with rat, bovine, and human PC. Caution is warranted in interpretation of immunoblots and immunohistochemical sections with this putative MDR1 gene-specific mAb.
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PMID:MDR1 gene-specific monoclonal antibody C494 cross-reacts with pyruvate carboxylase. 751 Oct 43

Multidrug resistance (MDR) is associated with overexpression of a 170 KD plasma membrane P-glycoprotein (P-gp), a putative energy-dependent efflux transporter that reduces intracellular accumulation of chemotherapeutic agents. For detection of P-gp expression in normal and malignant tissues, an MDR1-specific monoclonal antibody (MAb) JSB-1 has been used extensively. In this report we show that MAb JSB-1 crossreacts with a protein of M(r) approximately 130,000 present in rat liver mitochondrial inner membrane/matrix fractions. Peptide mapping and microsequencing identify this protein as pyruvate carboxylase (PC), an abundant mitochondrial enzyme. MAb JSB-1 also crossreacts with purified PC from bovine liver. Under immunoblotting conditions, this crossreactivity is partially abolished by pre-incubation of MAb JSB-1 with a 1000-fold molar excess of MAb C494 epitope-specific peptide (PNTLEGN), indicating that the epitope of MAb JSB-1 may either overlap with or be in close proximity to that of MAb C494. Immunohistochemical cross-reactivity was also demonstrated in cryosections of human skeletal muscle, a tissue known not to express P-gp. MAb JSB-1 strongly immunostained Type 1 fibers, the subtype known to contain abundant mitochondria. Use of MAb JSB-1 for detection of MDR1 P-gp expression should be approached with caution.
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PMID:Multidrug resistance P-glycoprotein monoclonal antibody JSB-1 crossreacts with pyruvate carboxylase. 853 34

P-glycoprotein (P-gp) is a 170 kDa transmembrane glycoprotein which plays a significant role in modulating pleomorphic or multiple drug resistance (MDR) in a wide variety of human cancers like renal and colorectal carcinoma. However, its role in modulating drug resistance in other types of cancer is less well defined. The purpose of this review is to critically examine the evidence that P-gp plays an important role in producing drug resistance in astrocytic gliomas. Malignant astrocytoma is clinically resistant to most types of cytotoxic drugs, including those associated with the MDR phenotype and the cross-resistance patterns of short-term cultures derived from malignant glioma are consistent with this phenotype. Consequently, it might be expected that this tumor would express high levels of P-gp. However, immunohistochemical findings from a number of previous studies have provided conflicting data about the expression of P-gp in these tumors, although P-gp has been consistently detected in normal brain in the endothelial cells in cerebral blood vessels and is thought to contribute to the blood-brain barrier phenomena. In order to determine if P-gp contributes to drug resistance in malignant astrocytoma, we undertook a study of P-gp expression in a panel of short-term cultures derived from these tumors in which we determined the in vitro chemosensitivity. However, immunocytochemical studies with a panel of antibodies which recognize both internal and external epitopes of the P-gp molecule have consistently failed to show the characteristic membrane staining associated with MDR in any of the cultures, including those markedly cross-resistant to vincristine and doxorubicin. One antibody, JSB-1, showed heterogeneous granular cytoplasmic staining which was unrelated to a particular pattern of drug resistance. This is probably because this antibody cross-reacts with a widely distributed cytoplasmic antigen, pyruvate carboxylase, which is present in abundance in normal astrocytes. The unexpectedly poor specificities of many of the antibodies thought to be specific for P-gp is reviewed in the context of malignant astrocytoma. In conclusion, the role of P-gp in producing drug resistance in malignant astrocytoma is questionable and further studies might more profitably concentrate on the mechanisms of resistance to DNA-damaging agents like the nitrosoureas, methylating agents or platinum-based drugs.
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PMID:Does P-glycoprotein play a role in clinical resistance of malignant astrocytoma? 1063 Mar 53