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Bleomycin upregulates expression of gamma-glutamylcysteine synthetase in pulmonary artery endothelial cells.
Am J Physiol Lung Cell Mol Physiol. 2002 Jun; 282(6):L1349-57.AJ

Abstract

The chemotherapeutic agent bleomycin induces pulmonary fibrosis through the generation of reactive oxygen species (ROS), which are thought to contribute to cellular damage and pulmonary injury. We hypothesized that bleomycin activates oxidative stress response pathways and regulates cellular glutathione (GSH). Bovine pulmonary artery endothelial cells exposed to bleomycin exhibit growth arrest and increased cellular GSH content. gamma-Glutamylcysteine synthetase (gamma-GCS) controls the key regulatory step in GSH synthesis, and Northern blots indicate that the gamma-GCS catalytic subunit [gamma-GCS heavy chain (gamma-GCS(h))] is upregulated by bleomycin within 3 h. The promoter for human gamma-GCS(h) contains consensus sites for nuclear factor-kappaB (NF-kappaB) and the antioxidant response element (ARE), both of which are activated in response to oxidative stress. Electrophoretic mobility shift assays show that bleomycin activates the transcription factor NF-kappaB as well as the ARE-binding factors Nrf-1 and -2. Nrf-1 and -2 activation by bleomycin is inhibited by the ROS quenching agent N-acetylcysteine (NAC), but not by U-0126, a MEK1/2 inhibitor that blocks bleomycin-induced MAPK activation. In contrast, NF-kappaB activation by bleomycin is inhibited by U-0126, but not by NAC. NAC and U-0126 both inhibit bleomycin-induced upregulation of gamma-GCS expression. These data suggest that bleomycin can activate oxidative stress response pathways and upregulate cellular GSH.

Authors+Show Affiliations

Pulmonary and Critical Care Division, Tupper Research Institute, New England Medical Center, Boston, Massachusetts 02111, USA. rday@lifespan.orgNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

12003792

Citation

Day, Regina M., et al. "Bleomycin Upregulates Expression of Gamma-glutamylcysteine Synthetase in Pulmonary Artery Endothelial Cells." American Journal of Physiology. Lung Cellular and Molecular Physiology, vol. 282, no. 6, 2002, pp. L1349-57.
Day RM, Suzuki YJ, Lum JM, et al. Bleomycin upregulates expression of gamma-glutamylcysteine synthetase in pulmonary artery endothelial cells. Am J Physiol Lung Cell Mol Physiol. 2002;282(6):L1349-57.
Day, R. M., Suzuki, Y. J., Lum, J. M., White, A. C., & Fanburg, B. L. (2002). Bleomycin upregulates expression of gamma-glutamylcysteine synthetase in pulmonary artery endothelial cells. American Journal of Physiology. Lung Cellular and Molecular Physiology, 282(6), L1349-57.
Day RM, et al. Bleomycin Upregulates Expression of Gamma-glutamylcysteine Synthetase in Pulmonary Artery Endothelial Cells. Am J Physiol Lung Cell Mol Physiol. 2002;282(6):L1349-57. PubMed PMID: 12003792.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Bleomycin upregulates expression of gamma-glutamylcysteine synthetase in pulmonary artery endothelial cells. AU - Day,Regina M, AU - Suzuki,Yuichiro J, AU - Lum,Julie M, AU - White,Alexander C, AU - Fanburg,Barry L, PY - 2002/5/11/pubmed PY - 2002/5/31/medline PY - 2002/5/11/entrez SP - L1349 EP - 57 JF - American journal of physiology. Lung cellular and molecular physiology JO - Am. J. Physiol. Lung Cell Mol. Physiol. VL - 282 IS - 6 N2 - The chemotherapeutic agent bleomycin induces pulmonary fibrosis through the generation of reactive oxygen species (ROS), which are thought to contribute to cellular damage and pulmonary injury. We hypothesized that bleomycin activates oxidative stress response pathways and regulates cellular glutathione (GSH). Bovine pulmonary artery endothelial cells exposed to bleomycin exhibit growth arrest and increased cellular GSH content. gamma-Glutamylcysteine synthetase (gamma-GCS) controls the key regulatory step in GSH synthesis, and Northern blots indicate that the gamma-GCS catalytic subunit [gamma-GCS heavy chain (gamma-GCS(h))] is upregulated by bleomycin within 3 h. The promoter for human gamma-GCS(h) contains consensus sites for nuclear factor-kappaB (NF-kappaB) and the antioxidant response element (ARE), both of which are activated in response to oxidative stress. Electrophoretic mobility shift assays show that bleomycin activates the transcription factor NF-kappaB as well as the ARE-binding factors Nrf-1 and -2. Nrf-1 and -2 activation by bleomycin is inhibited by the ROS quenching agent N-acetylcysteine (NAC), but not by U-0126, a MEK1/2 inhibitor that blocks bleomycin-induced MAPK activation. In contrast, NF-kappaB activation by bleomycin is inhibited by U-0126, but not by NAC. NAC and U-0126 both inhibit bleomycin-induced upregulation of gamma-GCS expression. These data suggest that bleomycin can activate oxidative stress response pathways and upregulate cellular GSH. SN - 1040-0605 UR - https://www.unboundmedicine.com/medline/citation/12003792/Bleomycin_upregulates_expression_of_gamma_glutamylcysteine_synthetase_in_pulmonary_artery_endothelial_cells_ L2 - http://journals.physiology.org/doi/full/10.1152/ajplung.00338.2001?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -