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3 results on '"Bcl xL"'

1. Inhibition of drug induced Fas ligand transcription and apoptosis by Bcl XL.

Author

Biswas, Rajat, Cha, Hyuk, Hardwick, J., and Srivastava, R.K.

Abstract

Fas/Fas ligand system triggers apoptosis in many cell types. Bcl XL overexpresion antagonizes Fas/Fas ligand mediated cell death. The mechanism by which Bcl-XL influences Fas mediated cell death is unclear. We have found that microtubule damaging drugs (e.g. Paclitaxel) induce apoptosis in a Fas/FasL dependent manner. Inhibition of Fas/FasL pathway by anti FasL antibody, mutant Fas or a dominant negative FADD blocks paclitaxel induced apoptosis. Paclitaxel induced apoptosis through activation of both caspase 8 and caspase 3. Overexpression of Bcl XL leads to inhibition of paclitaxel induced FasL expression and apoptosis. Bcl XL prevents the nuclear translocation of NFAT (nuclear factor of activated T lymphocytes) by inhibiting the activation of calcineurin, a calcium dependent phosphatase that must dephosphorylate NFAT for it to move to the nucleus. The loop domain in Bcl XL can suppress the anti apoptotic function of Bcl XL and may be a target for regulatory post translational modifications. Upon phosphorylation, Bcl XL loses its ability to bind with calcineurin. Without NFAT nuclear translocation, the FasL gene is not transcribed. Thus, paclitaxel and other drugs that disturb microtubule function kill cells, at least in part, through the induction of FasL, and Bcl XL mediated resistance to these agents is related to failure to induce FasL expression. [ABSTRACT FROM AUTHOR]

Published
2001
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2. Expression of COX-2, mPGE synthase 1, MDR-1 (P-GP) and BCL-XL: a molecular pathway of H pylori related-gastric carcinogenesis

Author

Gaetano Salvatore, Alfredo Budillon, Gaetano De Rosa, Fabiana Tatangelo, Gerardo Nardone, Paola Patrignani, Maria Di Benedetto, Maria G. Sciulli, Alba Rocco, Dino Vaira, Stefania Staibano, Federico Perna, NARDONE G, ROCCO A, VAIRA D., STAIBANO S, BUDILLON A, TATANGELO F, SCIALLI MG, PERNA F, SALVATORE G, DI BENEDETTO M, DE ROSA G, PATRIGNANI P, Nardone, GERARDO ANTONIO PIO, Rocco, Alba, Vaira, D, Staibano, Stefania, Budillon, A, Tatangelo, F, Sciulli, Mg, Perna, F, Salvatore, Gaetano, Di Benedetto, M, DE ROSA, Gaetano, and Patrignani, P.

Subjects
Adult, Male, medicine.medical_specialty, bcl-X Protein, medicine.disease_cause, Helicobacter Infections, Pathology and Forensic Medicine, Helicobacter pylory, Stomach Neoplasms, Gene expression, gastric carcinogenesi, medicine, Gastric mucosa, Humans, ATP Binding Cassette Transporter, Subfamily B, Member 1, MDR-1, Aged, Prostaglandin-E Synthases, Chi-Square Distribution, Helicobacter pylori, biology, Stomach, Membrane Proteins, Cancer, Bcl xL, Anatomical pathology, Middle Aged, medicine.disease, biology.organism_classification, Immunohistochemistry, Enzyme Activation, Intramolecular Oxidoreductases, Isoenzymes, mPGE-Synthase, medicine.anatomical_structure, Proto-Oncogene Proteins c-bcl-2, cyclooxygenase-2, Cyclooxygenase 2, Prostaglandin-Endoperoxide Synthases, Gastritis, Immunology, Cancer research, Female, Carcinogenesis
Abstract

Helicobacter pylori up-regulates cyclo-oxygenase-2 (COX-2) expression, which in turn is involved in tumourigenesis. Recently, a causal link between COX-2 and multidrug resistance 1 (MDR-1) gene expression, implicated in cancer chemoresistance, has been demonstrated. Thus, the expression of COX-2 and the downstream enzyme involved in PGE2 biosynthesis, microsomal PGE-synthase1 (mPGES1), was correlated with P-gp, the product of MDR-1, and the anti-apoptotic protein, Bcl-xL, in gastric biopsies from patients with H pylori infection and in patients with gastric cancer. In a retrospective analysis of endoscopic and pathology files, 40 H pylori-negative patients (Hp-), 50 H pylori-positive patients who responded to eradication therapy (Hp+R), 84 H pylori-positive patients who did not respond to eradication therapy (Hp+NR), and 30 patients with gastric cancer (18 intestinal and 12 diffuse types) were selected. COX-2, mPGES1, P-gp, and Bcl-xL were detected by immunohistochemistry. COX-2, mPGES1, P-gp, and Bcl-xL expression was undetectable in gastric mucosa from Hp- patients. By contrast, COX-2 and mPGES1 expression was detected in 42% and 44% of Hp+R patients, respectively, and in up to 66% (range 63-66%) of Hp+NR patients (p < 0.05). The expression of COX-2 and mPGES1 correlated significantly (p < 0.0001) with that of P-gp and Bcl-xL. High levels of COX-2, mPGES1, P-gp, and Bcl-xL expression were found in intestinal-type gastric cancer samples. In conclusion, H pylori-dependent induction of COX-2 and mPGES1 is associated with enhanced production of P-gp and Bcl-xL that may contribute to gastric tumourigenesis and resistance to therapy.

Published
2004

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