The role of H2O2 in the platelet-derived growth factor-induced transcription of the gamma-glutamylcysteine synthetase heavy subunit.
This study demonstrates that platelet-derived growth factor (PDGF) increases transcription of the gamma-glutamylcysteine synthetase (GCS) heavy subunit (GCS-HS) in NIH 3T3 fibroblasts via H2O2 and activation of protein kinase C (PKC). The data obtained using catalase, H2O2, phorbol-12-myristate 13-acetate (PMA) or a specific inhibitor of PKC demonstrate the possibility of a PDGF up-regulation pathway of GCS synthesis. Moreover, since PDGF mitogenic activity takes place through PKC activation and sphingosine-1-phosphate (S1P) production, the involvement of sphingosine kinase activity in the PDGF effect was also investigated. No clear direct relationship emerged between S1P production and any PDGF- or H2O2-induced increase in the GCS-HS mRNA level. However, for the first time, in S1P-stimulated NIH 3T3 cells, increased levels of GCS-HS mRNA were shown to be related to increases in the reduced glutathione synthesis rate similar to those obtained after PMA and PDGF stimulation.
D016475:3T3 Cells; D000818:Animals; D002374:Catalase / Q000378:metabolism; D003609:Dactinomycin / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D005721:Glutamate-Cysteine Ligase / Q000235:genetics*; D006861:Hydrogen Peroxide / Q000378:metabolism*; D008246:Lysophospholipids; D051379:Mice; D009097:Multienzyme Complexes / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism; D012333:RNA, Messenger; D015398:Signal Transduction / Q000502:physiology; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism; D013430:Sulfate Adenylyltransferase / Q000378:metabolism; D014158:Transcription, Genetic
D008246:Lysophospholipids; D009097:Multienzyme Complexes; D010982:Platelet-Derived Growth Factor; D012333:RNA, Messenger; C113697:sulfurylase kinase; D003609:Dactinomycin; C060506:sphingosine 1-phosphate; D006861:Hydrogen Peroxide; D002374:Catalase; D017853:Phosphotransferases (Alcohol Group Acceptor); D011493:Protein Kinase C; D013430:Sulfate Adenylyltransferase; D005721:Glutamate-Cysteine Ligase; D013110:Sphingosine