Stathmin mediates hepatocyte resistance to death from oxidative stress by down regulating JNK

Enpeng Zhao, Muhammad Amir, Yu Lin, Mark J. Czaja

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Article numbere109750
JournalPLoS One
Volume9
Issue number10
DOIs
StatePublished - Oct 6 2014

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Stathmin
Oxidative stress
JNK Mitogen-Activated Protein Kinases
mitogen-activated protein kinase
hepatocytes
Hepatocytes
Oxidative Stress
oxidative stress
death
menadione
Vitamin K 3
cell death
phosphorylation
Phosphorylation
Cell death
oxidants
microtubules
Cell Death
neoplasms
Oxidants

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Stathmin mediates hepatocyte resistance to death from oxidative stress by down regulating JNK. / Zhao, Enpeng; Amir, Muhammad; Lin, Yu; Czaja, Mark J.

In: PLoS One, Vol. 9, No. 10, e109750, 06.10.2014.

Research output: Contribution to journalArticle

Zhao, Enpeng ; Amir, Muhammad ; Lin, Yu ; Czaja, Mark J. / Stathmin mediates hepatocyte resistance to death from oxidative stress by down regulating JNK. In: PLoS One. 2014 ; Vol. 9, No. 10.
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