title: Rapamycin inhibits Erk1/2-mediated neuronal apoptosis caused by cadmium.
abstract: Cadmium (Cd), an environmental contaminant, causes neurodegenerative disorders. Recently we have shown that rapamycin prevents Cd-induced neuronal cell death by inhibiting mTOR signaling pathway. Here we found that rapamycin exerted its prevention against Cd-induced neuronal cell death also partially via blocking Erk1/2 pathway. Inhibiting Erk1/2 with PD98059 or silencing Erk1/2 potentiated rapamycin's inhibition of Cd-induced phosphorylation of Erk1/2 and apoptosis in neuronal cells. Both PP2A and PTEN/Akt were involved in the regulation of Erk1/2 activation and cell death triggered by Cd. Inhibition of PP2A with okadaic acid or ectopic expression of dominant negative PP2A attenuated rapamycin's inhibition of Cd-induced phospho-Erk1/2 and apoptosis, whereas over-expression of wild-type PP2A enhanced rapamycin's effects; Over-expression of wild-type PTEN or dominant negative Akt, or inhibition of Akt with Akt inhibitor X strengthened rapamycin's inhibition of Cd-induced phospho-Erk1/2 and cell death. Furthermore, expression of a rapamycin-resistant and kinase-active mTOR (mTOR-T) blocked rapamycin's inhibitory effects on Cd-induced inhibition of PP2A, down-regulation of PTEN, and activation of Akt, leading to Erk1/2 activation and cell death, whereas silencing mTOR mimicked rapamycin's effects. The results uncover that rapamycin inhibits Cd activation of Erk1/2-mediated neuronal apoptosis through intervening mTOR-PP2A/PTEN signaling network.
authors.affiliation: Jiangsu Key Laboratory for Molecular and Medical Biotechnology, Jiangsu Key Laboratory for Microbes and Functional Genomics, College of Life Sciences, Nanjing Normal University, Nanjing, PR China.
authors.forename: Chong
authors.initials: C
authors.lastname: Xu
authors.affiliation: Jiangsu Key Laboratory for Molecular and Medical Biotechnology, Jiangsu Key Laboratory for Microbes and Functional Genomics, College of Life Sciences, Nanjing Normal University, Nanjing, PR China.
authors.forename: Hai
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Jiangsu Key Laboratory for Molecular and Medical Biotechnology, Jiangsu Key Laboratory for Microbes and Functional Genomics, College of Life Sciences, Nanjing Normal University, Nanjing, PR China.
authors.forename: Chunxiao
authors.initials: C
authors.lastname: Liu
authors.affiliation: Jiangsu Key Laboratory for Molecular and Medical Biotechnology, Jiangsu Key Laboratory for Microbes and Functional Genomics, College of Life Sciences, Nanjing Normal University, Nanjing, PR China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Jiangsu Key Laboratory for Molecular and Medical Biotechnology, Jiangsu Key Laboratory for Microbes and Functional Genomics, College of Life Sciences, Nanjing Normal University, Nanjing, PR China.
authors.forename: Xiaoxue
authors.initials: X
authors.lastname: Wang
authors.affiliation: Jiangsu Key Laboratory for Molecular and Medical Biotechnology, Jiangsu Key Laboratory for Microbes and Functional Genomics, College of Life Sciences, Nanjing Normal University, Nanjing, PR China.
authors.forename: Wei
authors.initials: W
authors.lastname: Gao
authors.affiliation: Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, Shreveport, LA, USA.|Feist-Weiller Cancer Center, Louisiana State University Health Sciences Center, Shreveport, LA, USA.
authors.forename: Shile
authors.initials: S
authors.lastname: Huang
authors.affiliation: Jiangsu Key Laboratory for Molecular and Medical Biotechnology, Jiangsu Key Laboratory for Microbes and Functional Genomics, College of Life Sciences, Nanjing Normal University, Nanjing, PR China.
authors.forename: Long
authors.initials: L
authors.lastname: Chen
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000737:chemistry; D017209:Apoptosis; D002104:Cadmium / Q000737:chemistry*; D016923:Cell Death; D045744:Cell Line, Tumor; D004785:Environmental Pollutants; D005260:Female; D005419:Flavonoids / Q000737:chemistry; D020868:Gene Silencing; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D051379:Mice; D008813:Mice, Inbred ICR; D008856:Microscopy, Fluorescence; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000473:pathology*; D019319:Okadaic Acid / Q000737:chemistry; D054648:Protein Phosphatase 2 / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction; D020123:Sirolimus / Q000737:chemistry*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D000903:Antibiotics, Antineoplastic; D004785:Environmental Pollutants; D005419:Flavonoids; D002104:Cadmium; D019319:Okadaic Acid; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; C517189:PPP2CA protein, human; D054648:Protein Phosphatase 2; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; D020123:Sirolimus
keywords: Erk1/2; PP2A; PTEN; neuronal apoptosis; rapamycin