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.
Highlights
Stathmin 1 (STMN1) is a ubiquitous cytoplasmic protein that is a critical regulator of microtubules [1,2]
Stathmin is regulated by oxidant stress To begin to delineate the function of stathmin in hepatocyte death from oxidant stress, we examined whether levels of total stathmin or its phosphorylated forms are altered in response to injurious oxidative stress
In contrast to findings with hyperosmotic stress and tumor necrosis factor (TNF) in which knockdowns of stathmin reduced cell death [17,20], stathmin knockdown in hepatocytes under oxidative stress demonstrated that stathmin has a critical function in hepatocyte resistance to death from superoxide
Summary
Stathmin 1 (STMN1) is a ubiquitous cytoplasmic protein that is a critical regulator of microtubules [1,2]. Stathmin regulates the microtubule dynamics of the mitotic spindle and is most highly expressed in rapidly proliferating cells including many human cancers [3]. In the liver stathmin is expressed embryologically, lost after birth and re-expressed in hepatocytes and other cells in response to the regenerative stimulus of partial hepatectomy [5,6,7]. Stathmin is highly expressed in many other human cancers including breast, leukemia and prostate, and has been associated with poor histology, increased metastasis, increased drug resistance and decreased survival in these cancers as well [9,10,11,12]
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