Novel role for glutathione S-transferase pi. Regulator of protein S-Glutathionylation following oxidative and nitrosative stress.
Glutathione S-transferase Pi (GSTpi) is a marker protein in many cancers and high levels are linked to drug resistance, even when the selecting drug is not a substrate. S-Glutathionylation of proteins is critical to cellular stress response, but characteristics of the forward reaction are not known. Our results show that GSTpi potentiates S-glutathionylation reactions following oxidative and nitrosative stress in vitro and in vivo. Mutational analysis indicated that the catalytic activity of GST is required. GSTpi is itself redox-regulated. S-Glutathionylation on Cys47 and Cys101 autoregulates GSTpi, breaks ligand binding interactions with c-Jun NH2-terminal kinase (JNK), and causes GSTpi multimer formation, all critical to stress response. Catalysis of S-glutathionylation at low pK cysteines in proteins is a novel property for GSTpi and may be a cause for its abundance in tumors and cells resistant to a range of mechanistically unrelated anticancer drugs.
Townsend
Danyelle M
DM
Departments of Pharmaceutical and Biomedical Sciences and Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston, South Carolina 29425 and Novelos Inc., Newton, Massachusetts 02458.
Manevich
Yefim
Y
Departments of Pharmaceutical and Biomedical Sciences and Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston, South Carolina 29425 and Novelos Inc., Newton, Massachusetts 02458.
He
Lin
L
Departments of Pharmaceutical and Biomedical Sciences and Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston, South Carolina 29425 and Novelos Inc., Newton, Massachusetts 02458.
Hutchens
Steven
S
Departments of Pharmaceutical and Biomedical Sciences and Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston, South Carolina 29425 and Novelos Inc., Newton, Massachusetts 02458.
Pazoles
Christopher J
CJ
Departments of Pharmaceutical and Biomedical Sciences and Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston, South Carolina 29425 and Novelos Inc., Newton, Massachusetts 02458.
Tew
Kenneth D
KD
Departments of Pharmaceutical and Biomedical Sciences and Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston, South Carolina 29425 and Novelos Inc., Newton, Massachusetts 02458. Electronic address: tewk@musc.edu.
D000818:Animals; D019008:Drug Resistance, Neoplasm / Q000502:physiology; D005978:Glutathione / Q000235:genetics / Q000378:metabolism*; D051549:Glutathione S-Transferase pi / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D051379:Mice; D018345:Mice, Knockout; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology*; D011499:Protein Processing, Post-Translational / Q000502:physiology*
D009363:Neoplasm Proteins; C496556:GSTP1 protein, human; D051549:Glutathione S-Transferase pi; C496557:Gstp1 protein, mouse; D048031:JNK Mitogen-Activated Protein Kinases; D005978:Glutathione