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Hydrogen peroxide-induced neuronal apoptosis is associated with inhibition of protein phosphatase 2A and 5, leading to activation of MAPK pathway.
Int J Biochem Cell Biol. 2009 Jun; 41(6):1284-95.IJ

Abstract

Oxidative stress-induced neuronal apoptosis is a prominent feature found in neurodegenerative disorders. However, how oxidative stress induces neuronal apoptosis is not well understood. To address this question, undifferentiated and differentiated neuronal cell lines (PC12 and SH-SY5Y) were exposed to hydrogen peroxide (H(2)O(2)), a major oxidant generated when oxidative stress occurs. We observed that H(2)O(2) induced generation of reactive oxygen species (ROS), leading to apoptosis of the cells in a concentration- and time-dependent manner. H(2)O(2) rapidly activated the mitogen-activated protein kinases (MAPK) including extracellular signal-regulated kinase 1/2 (Erk1/2), c-Jun N-terminal kinase (JNK) and p38. Inhibition of Erk1/2, JNK or p38 with kinase inhibitors (U0126, SP600125 or PD169316, respectively), downregulation of Erk1/2 or p38 using RNA interference, or expression of dominant negative c-Jun partially prevented H(2)O(2)-induced apoptosis. Pretreatment with N-acetyl-L-cysteine (NAC) scavenged H(2)O(2)-induced ROS, blocking activation of MAPKs and cell death. Furthermore, we found that H(2)O(2)-induced ROS inhibited serine/threonine protein phosphatases 2A (PP2A) and 5 (PP5), which was abrogated by NAC. Overexpression of PP2A or PP5 partially prevented H(2)O(2)-activation of Erk/12, JNK and p38, as well as cell death. Similar results were observed in primary murine neurons as well. The results suggest that H(2)O(2)-induction of ROS inhibit PP2A and PP5, leading to activation of Erk1/2, JNK and p38 pathways thereby resulting in neuronal apoptosis. Our findings suggest that inhibitors of MAPKs (JNK, Erk1/2 and p38), activators of phosphatases (PP2A and PP5) or antioxidants may have potentials to prevent and treat oxidative stress-induced neurodegenerative diseases.

Authors+Show Affiliations

Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, 1501 Kings Highway, Shreveport, LA 71130-3932, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

19038359

Citation

Chen, Long, et al. "Hydrogen Peroxide-induced Neuronal Apoptosis Is Associated With Inhibition of Protein Phosphatase 2A and 5, Leading to Activation of MAPK Pathway." The International Journal of Biochemistry & Cell Biology, vol. 41, no. 6, 2009, pp. 1284-95.
Chen L, Liu L, Yin J, et al. Hydrogen peroxide-induced neuronal apoptosis is associated with inhibition of protein phosphatase 2A and 5, leading to activation of MAPK pathway. Int J Biochem Cell Biol. 2009;41(6):1284-95.
Chen, L., Liu, L., Yin, J., Luo, Y., & Huang, S. (2009). Hydrogen peroxide-induced neuronal apoptosis is associated with inhibition of protein phosphatase 2A and 5, leading to activation of MAPK pathway. The International Journal of Biochemistry & Cell Biology, 41(6), 1284-95. https://doi.org/10.1016/j.biocel.2008.10.029
Chen L, et al. Hydrogen Peroxide-induced Neuronal Apoptosis Is Associated With Inhibition of Protein Phosphatase 2A and 5, Leading to Activation of MAPK Pathway. Int J Biochem Cell Biol. 2009;41(6):1284-95. PubMed PMID: 19038359.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Hydrogen peroxide-induced neuronal apoptosis is associated with inhibition of protein phosphatase 2A and 5, leading to activation of MAPK pathway. AU - Chen,Long, AU - Liu,Lei, AU - Yin,Jun, AU - Luo,Yan, AU - Huang,Shile, Y1 - 2008/11/06/ PY - 2008/06/06/received PY - 2008/10/06/revised PY - 2008/10/31/accepted PY - 2008/11/29/entrez PY - 2008/11/29/pubmed PY - 2009/10/27/medline SP - 1284 EP - 95 JF - The international journal of biochemistry & cell biology JO - Int J Biochem Cell Biol VL - 41 IS - 6 N2 - Oxidative stress-induced neuronal apoptosis is a prominent feature found in neurodegenerative disorders. However, how oxidative stress induces neuronal apoptosis is not well understood. To address this question, undifferentiated and differentiated neuronal cell lines (PC12 and SH-SY5Y) were exposed to hydrogen peroxide (H(2)O(2)), a major oxidant generated when oxidative stress occurs. We observed that H(2)O(2) induced generation of reactive oxygen species (ROS), leading to apoptosis of the cells in a concentration- and time-dependent manner. H(2)O(2) rapidly activated the mitogen-activated protein kinases (MAPK) including extracellular signal-regulated kinase 1/2 (Erk1/2), c-Jun N-terminal kinase (JNK) and p38. Inhibition of Erk1/2, JNK or p38 with kinase inhibitors (U0126, SP600125 or PD169316, respectively), downregulation of Erk1/2 or p38 using RNA interference, or expression of dominant negative c-Jun partially prevented H(2)O(2)-induced apoptosis. Pretreatment with N-acetyl-L-cysteine (NAC) scavenged H(2)O(2)-induced ROS, blocking activation of MAPKs and cell death. Furthermore, we found that H(2)O(2)-induced ROS inhibited serine/threonine protein phosphatases 2A (PP2A) and 5 (PP5), which was abrogated by NAC. Overexpression of PP2A or PP5 partially prevented H(2)O(2)-activation of Erk/12, JNK and p38, as well as cell death. Similar results were observed in primary murine neurons as well. The results suggest that H(2)O(2)-induction of ROS inhibit PP2A and PP5, leading to activation of Erk1/2, JNK and p38 pathways thereby resulting in neuronal apoptosis. Our findings suggest that inhibitors of MAPKs (JNK, Erk1/2 and p38), activators of phosphatases (PP2A and PP5) or antioxidants may have potentials to prevent and treat oxidative stress-induced neurodegenerative diseases. SN - 1878-5875 UR - https://www.unboundmedicine.com/medline/citation/19038359/Hydrogen_peroxide_induced_neuronal_apoptosis_is_associated_with_inhibition_of_protein_phosphatase_2A_and_5_leading_to_activation_of_MAPK_pathway_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1357-2725(08)00456-1 DB - PRIME DP - Unbound Medicine ER -