Protein tyrosine phosphatase 1B modulates GSK3ß/Nrf2 and IGF-1R signalling pathways in acetaminophen-induced hepatotoxicity
Acute hepatic failure secondary to acetaminophen (APAP) poisoning is associated with high mortality. Protein tyrosine phosphatase 1B (PTP1B) is a negative regulator of tyrosine kinase growth factor signaling. In the liver, this pathway confers protection against injury. However, the involvement of PTP1B in the intracellular networks activated by APAP is unknown. We have assessed PTP1B expression in APAP-induced liver failure in humans and its role in the molecular mechanisms that regulate the balance between cell death and survival in human and mouse hepatocytes, as well as in a mouse model of APAPinduced hepatotoxicity. PTP1B expression was increased in human liver tissue removed during liver transplant from patients for APAP overdose. PTP1B was upregulated by APAP in primary human and mouse hepatocytes together with the activation of c-jun (NH2) terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38 MAPK), resulting in cell death. Conversely, Akt phosphorylation and the antiapoptotic Bcl2 family members BclxL and Mcl1 were decreased. PTP1B deficiency in mouse protects hepatocytes against APAP-induced cell death, preventing glutathione depletion, reactive oxygen species (ROS) generation and activation of JNK and p38 MAPK. APAP-treated PTP1B / hepatocytes showed enhanced antioxidant defense through the glycogen synthase kinase 3 (GSK3)b/Src kinase family (SKF) axis, delaying tyrosine phosphorylation of the transcription factor nuclear factor-erythroid 2-related factor (Nrf2) and its nuclear exclusion, ubiquitination and degradation. Insulin-like growth factor-I receptor-mediated signaling decreased in APAP-treated wild-type hepatocytes, but was maintained in PTP1B / cells or in wild-type hepatocytes with reduced PTP1B levels by RNA interference. Likewise, both signaling cascades were modulated in mice, resulting in less severe APAP hepatotoxicity in PTP1B / mice. Our results demonstrated that PTP1B is a central player of the mechanisms triggered by APAP in hepatotoxicity, suggesting a novel therapeutic target against APAPinduced liver failure. Cell
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2013
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Subjects: | Liver injury, Tyrosine phosphorylation, Oxidative stress, Survival signaling, Apoptosis, |
Online Access: | http://hdl.handle.net/10261/111439 |
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dig-ictan-es-10261-1114392019-09-04T08:56:17Z Protein tyrosine phosphatase 1B modulates GSK3ß/Nrf2 and IGF-1R signalling pathways in acetaminophen-induced hepatotoxicity Mobasher, Maysa A. Ramos, Sonia Goya, Luis Valverde, M. A. Liver injury Tyrosine phosphorylation Oxidative stress Survival signaling Apoptosis Acute hepatic failure secondary to acetaminophen (APAP) poisoning is associated with high mortality. Protein tyrosine phosphatase 1B (PTP1B) is a negative regulator of tyrosine kinase growth factor signaling. In the liver, this pathway confers protection against injury. However, the involvement of PTP1B in the intracellular networks activated by APAP is unknown. We have assessed PTP1B expression in APAP-induced liver failure in humans and its role in the molecular mechanisms that regulate the balance between cell death and survival in human and mouse hepatocytes, as well as in a mouse model of APAPinduced hepatotoxicity. PTP1B expression was increased in human liver tissue removed during liver transplant from patients for APAP overdose. PTP1B was upregulated by APAP in primary human and mouse hepatocytes together with the activation of c-jun (NH2) terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38 MAPK), resulting in cell death. Conversely, Akt phosphorylation and the antiapoptotic Bcl2 family members BclxL and Mcl1 were decreased. PTP1B deficiency in mouse protects hepatocytes against APAP-induced cell death, preventing glutathione depletion, reactive oxygen species (ROS) generation and activation of JNK and p38 MAPK. APAP-treated PTP1B / hepatocytes showed enhanced antioxidant defense through the glycogen synthase kinase 3 (GSK3)b/Src kinase family (SKF) axis, delaying tyrosine phosphorylation of the transcription factor nuclear factor-erythroid 2-related factor (Nrf2) and its nuclear exclusion, ubiquitination and degradation. Insulin-like growth factor-I receptor-mediated signaling decreased in APAP-treated wild-type hepatocytes, but was maintained in PTP1B / cells or in wild-type hepatocytes with reduced PTP1B levels by RNA interference. Likewise, both signaling cascades were modulated in mice, resulting in less severe APAP hepatotoxicity in PTP1B / mice. Our results demonstrated that PTP1B is a central player of the mechanisms triggered by APAP in hepatotoxicity, suggesting a novel therapeutic target against APAPinduced liver failure. Cell Peer Reviewed 2015-02-27T07:31:33Z 2015-02-27T07:31:33Z 2013 2015-02-27T07:31:33Z artículo http://purl.org/coar/resource_type/c_6501 issn: 1476-5403 Cell Death and Differentiation 4 (2013) http://hdl.handle.net/10261/111439 none |
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Liver injury Tyrosine phosphorylation Oxidative stress Survival signaling Apoptosis Liver injury Tyrosine phosphorylation Oxidative stress Survival signaling Apoptosis |
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Liver injury Tyrosine phosphorylation Oxidative stress Survival signaling Apoptosis Liver injury Tyrosine phosphorylation Oxidative stress Survival signaling Apoptosis Mobasher, Maysa A. Ramos, Sonia Goya, Luis Valverde, M. A. Protein tyrosine phosphatase 1B modulates GSK3ß/Nrf2 and IGF-1R signalling pathways in acetaminophen-induced hepatotoxicity |
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Acute hepatic failure secondary to acetaminophen (APAP) poisoning is associated with high mortality. Protein tyrosine phosphatase 1B (PTP1B) is a negative regulator of tyrosine kinase growth factor signaling. In the liver, this pathway confers protection against injury. However, the involvement of PTP1B in the intracellular networks activated by APAP is unknown. We have assessed PTP1B expression in APAP-induced liver failure in humans and its role in the molecular mechanisms that regulate the balance between cell death and survival in human and mouse hepatocytes, as well as in a mouse model of APAPinduced hepatotoxicity. PTP1B expression was increased in human liver tissue removed during liver transplant from patients for APAP overdose. PTP1B was upregulated by APAP in primary human and mouse hepatocytes together with the activation of c-jun (NH2) terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38 MAPK), resulting in cell death. Conversely, Akt phosphorylation and the antiapoptotic Bcl2 family members BclxL and Mcl1 were decreased. PTP1B deficiency in mouse protects hepatocytes against APAP-induced cell death, preventing glutathione depletion, reactive oxygen species (ROS) generation and activation of JNK and p38 MAPK. APAP-treated PTP1B / hepatocytes showed enhanced antioxidant defense through the glycogen synthase kinase 3 (GSK3)b/Src kinase family (SKF) axis, delaying tyrosine phosphorylation of the transcription factor nuclear factor-erythroid 2-related factor (Nrf2) and its nuclear exclusion, ubiquitination and degradation. Insulin-like growth factor-I receptor-mediated signaling decreased in APAP-treated wild-type hepatocytes, but was maintained in PTP1B / cells or in wild-type hepatocytes with reduced PTP1B levels by RNA interference. Likewise, both signaling cascades were modulated in mice, resulting in less severe APAP hepatotoxicity in PTP1B / mice. Our results demonstrated that PTP1B is a central player of the mechanisms triggered by APAP in hepatotoxicity, suggesting a novel therapeutic target against APAPinduced liver failure. Cell |
format |
artículo |
topic_facet |
Liver injury Tyrosine phosphorylation Oxidative stress Survival signaling Apoptosis |
author |
Mobasher, Maysa A. Ramos, Sonia Goya, Luis Valverde, M. A. |
author_facet |
Mobasher, Maysa A. Ramos, Sonia Goya, Luis Valverde, M. A. |
author_sort |
Mobasher, Maysa A. |
title |
Protein tyrosine phosphatase 1B modulates GSK3ß/Nrf2 and IGF-1R signalling pathways in acetaminophen-induced hepatotoxicity |
title_short |
Protein tyrosine phosphatase 1B modulates GSK3ß/Nrf2 and IGF-1R signalling pathways in acetaminophen-induced hepatotoxicity |
title_full |
Protein tyrosine phosphatase 1B modulates GSK3ß/Nrf2 and IGF-1R signalling pathways in acetaminophen-induced hepatotoxicity |
title_fullStr |
Protein tyrosine phosphatase 1B modulates GSK3ß/Nrf2 and IGF-1R signalling pathways in acetaminophen-induced hepatotoxicity |
title_full_unstemmed |
Protein tyrosine phosphatase 1B modulates GSK3ß/Nrf2 and IGF-1R signalling pathways in acetaminophen-induced hepatotoxicity |
title_sort |
protein tyrosine phosphatase 1b modulates gsk3ß/nrf2 and igf-1r signalling pathways in acetaminophen-induced hepatotoxicity |
publishDate |
2013 |
url |
http://hdl.handle.net/10261/111439 |
work_keys_str_mv |
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