Stathmin mediates hepatocyte resistance to death from oxidative stress by down regulating JNK.
Stathmin 1 performs a critical function in cell proliferation by regulating microtubule polymerization. This proliferative function is thought to explain the frequent overexpression of stathmin in human cancer and its correlation with a bad prognosis. Whether stathmin also functions in cell death pa...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2014-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC4186850?pdf=render |
| _version_ | 1828381394068307968 |
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| author | Enpeng Zhao Muhammad Amir Yu Lin Mark J Czaja |
| author_facet | Enpeng Zhao Muhammad Amir Yu Lin Mark J Czaja |
| author_sort | Enpeng Zhao |
| collection | DOAJ |
| description | Stathmin 1 performs a critical function in cell proliferation by regulating microtubule polymerization. This proliferative function is thought to explain the frequent overexpression of stathmin in human cancer and its correlation with a bad prognosis. Whether stathmin also functions in cell death pathways is unclear. Stathmin regulates microtubules in part by binding free tubulin, a process inhibited by stathmin phosphorylation from kinases including c-Jun N-terminal kinase (JNK). The involvement of JNK activation both in stathmin phosphorylation, and in hepatocellular resistance to oxidative stress, led to an examination of the role of stathmin/JNK crosstalk in oxidant-induced hepatocyte death. Oxidative stress from menadione-generated superoxide induced JNK-dependent stathmin phosphorylation at Ser-16, Ser-25 and Ser-38 in hepatocytes. A stathmin knockdown sensitized hepatocytes to both apoptotic and necrotic cell death from menadione without altering levels of oxidant generation. The absence of stathmin during oxidative stress led to JNK overactivation that was the mechanism of cell death as a concomitant knockdown of JNK1 or JNK2 blocked death. Hepatocyte death from JNK overactivation was mediated by the effects of JNK on mitochondria. Mitochondrial outer membrane permeabilization occurred in stathmin knockdown cells at low concentrations of menadione that triggered apoptosis, whereas mitochondrial β-oxidation and ATP homeostasis were compromised at higher, necrotic menadione concentrations. Stathmin therefore mediates hepatocyte resistance to death from oxidative stress by down regulating JNK and maintaining mitochondrial integrity. These findings demonstrate a new mechanism by which stathmin promotes cell survival and potentially tumor growth. |
| first_indexed | 2024-12-10T04:14:57Z |
| format | Article |
| id | doaj.art-2de87c7ab70a45f79430c964a1dab3ca |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-10T04:14:57Z |
| publishDate | 2014-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-2de87c7ab70a45f79430c964a1dab3ca2022-12-22T02:02:37ZengPublic Library of Science (PLoS)PLoS ONE1932-62032014-01-01910e10975010.1371/journal.pone.0109750Stathmin mediates hepatocyte resistance to death from oxidative stress by down regulating JNK.Enpeng ZhaoMuhammad AmirYu LinMark J CzajaStathmin 1 performs a critical function in cell proliferation by regulating microtubule polymerization. This proliferative function is thought to explain the frequent overexpression of stathmin in human cancer and its correlation with a bad prognosis. Whether stathmin also functions in cell death pathways is unclear. Stathmin regulates microtubules in part by binding free tubulin, a process inhibited by stathmin phosphorylation from kinases including c-Jun N-terminal kinase (JNK). The involvement of JNK activation both in stathmin phosphorylation, and in hepatocellular resistance to oxidative stress, led to an examination of the role of stathmin/JNK crosstalk in oxidant-induced hepatocyte death. Oxidative stress from menadione-generated superoxide induced JNK-dependent stathmin phosphorylation at Ser-16, Ser-25 and Ser-38 in hepatocytes. A stathmin knockdown sensitized hepatocytes to both apoptotic and necrotic cell death from menadione without altering levels of oxidant generation. The absence of stathmin during oxidative stress led to JNK overactivation that was the mechanism of cell death as a concomitant knockdown of JNK1 or JNK2 blocked death. Hepatocyte death from JNK overactivation was mediated by the effects of JNK on mitochondria. Mitochondrial outer membrane permeabilization occurred in stathmin knockdown cells at low concentrations of menadione that triggered apoptosis, whereas mitochondrial β-oxidation and ATP homeostasis were compromised at higher, necrotic menadione concentrations. Stathmin therefore mediates hepatocyte resistance to death from oxidative stress by down regulating JNK and maintaining mitochondrial integrity. These findings demonstrate a new mechanism by which stathmin promotes cell survival and potentially tumor growth.http://europepmc.org/articles/PMC4186850?pdf=render |
| spellingShingle | Enpeng Zhao Muhammad Amir Yu Lin Mark J Czaja Stathmin mediates hepatocyte resistance to death from oxidative stress by down regulating JNK. PLoS ONE |
| title | Stathmin mediates hepatocyte resistance to death from oxidative stress by down regulating JNK. |
| title_full | Stathmin mediates hepatocyte resistance to death from oxidative stress by down regulating JNK. |
| title_fullStr | Stathmin mediates hepatocyte resistance to death from oxidative stress by down regulating JNK. |
| title_full_unstemmed | Stathmin mediates hepatocyte resistance to death from oxidative stress by down regulating JNK. |
| title_short | Stathmin mediates hepatocyte resistance to death from oxidative stress by down regulating JNK. |
| title_sort | stathmin mediates hepatocyte resistance to death from oxidative stress by down regulating jnk |
| url | http://europepmc.org/articles/PMC4186850?pdf=render |
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