Mixed lineage kinase 3 negatively regulates IKK activity and enhances etoposide-induced cell death

Cole, Eric T.; Zhan, Yu; Saab, Widian F. Abi; Korchnak, Amanda; Ashburner, Brian P.; Chadee, Deborah N.

doi:10.1016/j.bbamcr.2009.09.014

Cited by 11 publications

(4 citation statements)

References 29 publications

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“…As expected HFHC diet‐fed WT mice have increased JNK phosphorylation, which was reduced in the Mlk3 −/− mice on the same diet. MLK3 has been implicated in the activation of apoptotic cell death secondary to various stressful stimuli in neuronal, ovarian, pancreatic and hepatoma cells , on the other hand, hepatocytes depleted of MLK3 were partially protected from SFA‐induced apoptosis , a prominent feature of NASH . Consistent with the human disease, serum ALT and TUNEL‐positive liver cells were increased in mice fed the HFHC diet.…”

Section: Discussionmentioning

confidence: 75%

Mixed lineage kinase 3 deficient mice are protected against the high fat high carbohydrate diet‐induced steatohepatitis

Ibrahim

Gores

Hirsova

et al. 2013

Liver International

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Background C-Jun N-terminal kinase (JNK) activation is pivotal in the development of nonalcoholic steatohepatitis (NASH). Mixed lineage kinase 3 (MLK) 3 is one of the mitogen activated protein kinase kinase kinase (MAP3K) that mediates JNK activation in the liver. Despite this concept, the role of MLK3 in modulating liver injury during nutrient excess has not been explored. Aims our aim was to determine if MLK3 deficient mice were protected against high fat high carbohydrate (HFHC) diet-induced NASH. Methods We employed eight-week-old Mlk3−/− male C57BL/6J mice, and wild type (WT) mice C57BL/6J as controls. Mice were fed a HFHC or a chow diet adlib for 16 weeks. Results Hepatic JNK activating phosphorylation was readily absent in the Mlk3−/− mice fed the HFHC diet, but not in WT mice. This inhibition of JNK activation was hepatoprotective. Despite a comparable increase in weight gain, hepatic steatosis by histological examination and hepatic triglyceride quantification was reduced in HFHC diet-fed Mlk3−/− mice compared to WT mice. In addition, compared to the WT mice, HFHC diet-fed Mlk3−/− mice had significantly attenuated liver injury as manifested by reduced ALT levels, hepatocyte apoptosis, markers of hepatic inflammation, and indices of hepatic fibrogenesis. Conclusion our results suggest that loss of MLK3 in mice is protective against HFHC diet-induced NASH, in a weight-independent fashion, through attenuation of JNK activation. MLK3 is a potential therapeutic target for the treatment of human NASH.

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Section: Discussionmentioning

confidence: 75%

Mixed lineage kinase 3 deficient mice are protected against the high fat high carbohydrate diet‐induced steatohepatitis

Ibrahim

Gores

Hirsova

et al. 2013

Liver International

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“…Instead, we show that decreased JNK activation in Cdc42/Rac1 and MLK3 deficient cells correlates with attenuation of palmitate-induced cell death, suggesting a role for MLK3 in SFA-induced death in hepatocytes. Indeed, MLK3 has been shown to mediate JNK activation in some forms of stress-induced apoptosis [10, 16, 31, 48]. Interestingly, it was recently demonstrated that GSK-3 promotes JNK-dependent lipoapotosis [17].…”

Section: Discussionmentioning

confidence: 99%

Cdc42 and Rac1 are major contributors to the saturated fatty acid-stimulated JNK pathway in hepatocytes

Sharma

Urano

Jaeschke

2012

Journal of Hepatology

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Background & Aims Saturated free fatty acid (SFA)-stimulated c-Jun NH2-terminal kinase (JNK) activation is associated with the pathogenesis of non-alcoholic fatty liver disease (NAFLD). However, the mechanisms responsible for the effects of SFA are incompletely understood. The goal of this study was to determine the molecular mechanisms by which SFA induce JNK activation in hepatocytes. Methods We used siRNA-mediated knockdown in Hepa1c1c7 and AML12 cell lines, as well as primary mouse hepatocytes for these studies. Results The current model for JNK activation by SFA involves endoplasmic reticulum (ER) stress, which induces JNK activation through an inositol requiring enzyme 1 (IRE1α)/Apoptosis Regulating Kinase 1 (ASK1)–dependent mechanism. Here, we find that SFA-induced JNK activation is not inhibited in the absence of IRE1α and ASK1. Instead we show that activation of the small GTP-binding proteins Cdc42 and Rac1 is required for SFA-stimulated MLK3-dependent activation of JNK in hepatocytes. In addition, we demonstrate that SFA-induced cell death in hepatocytes is independent of IRE1α, but dependent on Cdc42, Rac1 and MLK3. Conclusions Our results demonstrate that Cdc42 and Rac1, rather than ER stress, are important components of a SFA-stimulated signaling pathway that regulates MLK3-dependent activation of JNK in hepatocytes.

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“…Interestingly, PEA3 expression is also elevated in advanced metastatic ovarian cancer [36]. Some MMP genes are also transcriptionally activated by NF-3B; however, our previous studies indicate that MLK3 does not promote NF-κB activation, and therefore it is not likely a major contributor to MLK3-dependent activation of MMP gene expression [37]. …”

Section: Discussionmentioning

confidence: 99%

Mixed lineage kinase 3 is required for matrix metalloproteinase expression and invasion in ovarian cancer cells

Zhan

Saab

Modi

et al. 2012

Experimental Cell Research

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Mixed lineage kinase 3 (MLK3) is a mitogen-activated protein kinase kinase kinase (MAP3K) that activates MAPK signaling pathways and regulates cellular responses such as proliferation, migration and apoptosis. Here we report high levels of total and phospho-MLK3 in ovarian cancer cell lines in comparison to immortalized nontumorigenic ovarian epithelial cell lines. Using small interfering RNA (siRNA)-mediated gene silencing, we determined that MLK3 is required for the invasion of SKOV3 and HEY1B ovarian cancer cells. Furthermore, mlk3 silencing substantially reduced matrix metalloproteinase (MMP) -1, -2, -9 and -12 gene expression and MMP-2 and -9 activities in SKOV3 and HEY1B ovarian cancer cells. MMP-1, -2, -9 and-12 expression, and MLK3-induced activation of MMP-2 and MMP-9 requires both extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase activities. In addition, inhibition of activator protein-1 (AP-1) reduced MMP-1, MMP-9 and MMP-12 gene expression. Collectively, these findings establish MLK3 as an important regulator of MMP expression and invasion in ovarian cancer cells.

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Mixed lineage kinase 3 negatively regulates IKK activity and enhances etoposide-induced cell death

Cited by 11 publications

References 29 publications

Mixed lineage kinase 3 deficient mice are protected against the high fat high carbohydrate diet‐induced steatohepatitis

Mixed lineage kinase 3 deficient mice are protected against the high fat high carbohydrate diet‐induced steatohepatitis

Cdc42 and Rac1 are major contributors to the saturated fatty acid-stimulated JNK pathway in hepatocytes

Mixed lineage kinase 3 is required for matrix metalloproteinase expression and invasion in ovarian cancer cells

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