title: Inhibition of PP2A and the consequent activation of JNK/c-Jun are involved in tributyltin-induced apoptosis in human amnionic cells.
abstract: Tributyltin (TBT), a highly toxic environmental contaminant, has been shown to induce mitochondrial-dependent apoptosis in several mammalian cells. However, the upstream signal transduction pathways involved in TBT-induced apoptosis are still not fully elucidated. In this study, the protein phosphatase (PP) 2A, microtubule organization, and mitogen-activated protein kinases (MAPKs), including JNK, p38 and their downstream transcription factors, c-Jun and ATF-2, respectively, were investigated in human amnionic cells treated by TBT. Furthermore, the activation of procaspase-3 after blocking either one of these MAPK pathways was also observed. The results showed that TBT effectively induced apoptosis characterized by caspase-3 activation. In apoptotic cells, the inhibition of PP2A activity and microtubule depolymerization was detected. Additionally, JNK and p38, as well as their downstream targets, c-Jun and ATF-2, were activated. Moreover, a JNK inhibitor, but not p38 inhibitor, significantly reduced caspase-3 activation. It can be concluded that the inhibition of PP2A may (1) play as a role in the activation of JNK and c-Jun and the concomitant promotion of microtubule depolymerization and (2) lead to the activation of caspase-3 in TBT-induced apoptotic cells. The results of this study suggest a critical role of PP2A in the TBT toxicity mechanism.
authors.affiliation: Department of Biochemistry and Genetics, School of medicine, Zhejiang University, 388 Yu Hang Tang Road, 310058, Hangzhou, China.
authors.forename: Yali
authors.initials: Y
authors.lastname: Zhang
authors.forename: Jing
authors.initials: J
authors.lastname: Liang
authors.forename: Lijun
authors.initials: L
authors.lastname: Sun
authors.forename: Zonglou
authors.initials: Z
authors.lastname: Guo
authors.forename: Lihong
authors.initials: L
authors.lastname: Xu
mesh_terms: D051698:Activating Transcription Factor 2 / Q000378:metabolism; D000650:Amnion / Q000166:cytology*; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D002460:Cell Line; D004785:Environmental Pollutants / Q000633:toxicity*; D004789:Enzyme Activation; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008870:Microtubules / Q000187:drug effects / Q000648:ultrastructure; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D010766:Phosphorylation; D054648:Protein Phosphatase 2 / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects; D014220:Trialkyltin Compounds / Q000633:toxicity*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C497105:ATF2 protein, human; D051698:Activating Transcription Factor 2; D004785:Environmental Pollutants; D014220:Trialkyltin Compounds; C011559:tributyltin; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D054648:Protein Phosphatase 2; D053148:Caspase 3