ABSTRACT
Irreversible oxidation of Cys residues to sulfinic/sulfonic forms typically impairs protein function. We found that persulfidation (CysSSH) protects Cys from irreversible oxidative loss of function by the formation of CysSSO1-3H derivatives that can subsequently be reduced back to native thiols. Reductive reactivation of oxidized persulfides by the thioredoxin system was demonstrated in albumin, Prx2, and PTP1B. In cells, this mechanism protects and regulates key proteins of signaling pathways, including Prx2, PTEN, PTP1B, HSP90, and KEAP1. Using quantitative mass spectrometry, we show that (i) CysSSH and CysSSO3H species are abundant in mouse liver and enzymatically regulated by the glutathione and thioredoxin systems and (ii) deletion of the thioredoxin-related protein TRP14 in mice altered CysSSH levels on a subset of proteins, predicting a role for TRP14 in persulfide signaling. Furthermore, selenium supplementation, polysulfide treatment, or knockdown of TRP14 mediated cellular responses to EGF, suggesting a role for TrxR1/TRP14-regulated oxidative persulfidation in growth factor responsiveness.
Subject(s)
Cysteine/genetics , Oxidation-Reduction/drug effects , Thioredoxin Reductase 1/genetics , Thioredoxins/genetics , Animals , Cysteine/chemistry , Epidermal Growth Factor/genetics , HSP90 Heat-Shock Proteins/genetics , Homeodomain Proteins/chemistry , Homeodomain Proteins/genetics , Humans , Kelch-Like ECH-Associated Protein 1/genetics , Mice , PTEN Phosphohydrolase/genetics , Protein Tyrosine Phosphatase, Non-Receptor Type 1/genetics , Selenium/pharmacology , Signal Transduction/drug effects , Sulfides/metabolism , Sulfides/pharmacology , Thioredoxin Reductase 1/chemistry , Thioredoxins/chemistryABSTRACT
Mammalian Ste20-like kinase-1 (MST1) kinase mediates H2O2-induced cell death by anticancer drugs such as cisplatin in a p53-dependent manner. However, the mechanism underlying MST1 activation by H2O2 remains unknown. Here we show that peroxiredoxin-I (PRX-I) is an essential intermediate in H2O2-induced MST1 activation and cisplatin-induced cell death through p53. Cell stimulation with H2O2 resulted in PRX-I oxidation to form homo-oligomers and interaction with MST1, leading to MST1 autophosphorylation and augmentation of kinase activity. In addition, RNA interference knockdown experiments indicated that endogenous PRX-I is required for H2O2-induced MST1 activation. Live-cell imaging showed H2O2 generation by cisplatin treatment, which likewise caused PRX-I oligomer formation, MST1 activation and cell death. Cisplatin-induced PRX-I oligomer formation was not observed in embryonic fibroblasts obtained from p53-knockout mice, confirming the importance of p53. Indeed, ectopic expression of p53 induced PRX-I oligomer formation and cell death, both of which were cancelled by the antioxidant NAC. Moreover, we succeeded in reconstituting H2O2-induced MST1 activation in vitro, using purified PRX-I and MST1 proteins. Collectively, our results show a novel PRX-I function to cause cell death in response to high levels of oxidative stress by activating MST1, which underlies the p53-dependent cytotoxicity caused by anticancer agents.
Subject(s)
Apoptosis , Peroxiredoxins/metabolism , Protein Serine-Threonine Kinases/metabolism , Tumor Suppressor Protein p53/metabolism , Antineoplastic Agents/pharmacology , Biopolymers , Cisplatin/pharmacology , Enzyme Activation , Humans , Hydrogen Peroxide/metabolism , Intracellular Signaling Peptides and Proteins , Phosphorylation , RNA InterferenceSubject(s)
Bronchial Neoplasms , Leiomyoma , Leiomyosarcoma , Lung Neoplasms , Bronchial Neoplasms/diagnosis , Bronchial Neoplasms/therapy , Combined Modality Therapy , Diagnosis, Differential , Humans , Leiomyoma/diagnosis , Leiomyoma/therapy , Leiomyosarcoma/diagnosis , Leiomyosarcoma/therapy , Lung Neoplasms/diagnosis , Lung Neoplasms/therapy , PrognosisABSTRACT
Tracheobronchomalacia in 3 children and 4 adults was reviewed, and operative indications were investigated. Tracheobronchomalacia in children differed from that in adults in that the lesion was localized and spontaneous healing was effected by cartilage growth and hardening. In adults, tracheobronchomalacia was characterized by a notch on the expiratory flow volume curve and higher V peak of inspiratory flow volume curve than that of expiratory curve. Operative indications for tracheobronchomalacia are BP higher than 28.2 cmH2O and delta CT higher than 15.4 cmH2O. Of 2 patients with tracheobronchomalacia in whom airway pressure was measured, one was a candidate for operation, and in the other, surgery was contraindicated because of low BP due to chronic obstructive pulmonary disease.
Subject(s)
Bronchial Diseases/surgery , Tracheal Diseases/surgery , Adult , Aged , Female , Humans , Infant , Infant, Newborn , Male , Middle AgedABSTRACT
The distribution of thymic tissue in the anterior mediastinal, retrocarinal, and preaortic fat was examined histologically in 27 autopsy subjects. Thymic tissue was found in the anterior mediastinal fat in 12 subjects (44.4%), in the retrocarinal fat in two (7.4%), and in the preaortic fat in none. The finding of ectopic thymic tissue in these areas has not been reported previously, would appear to be surgically inaccessible via a median sternotomy, and may be responsible in part for some of the failures of thymectomy in the treatment of myasthenia gravis.
