c-Jun N-terminal Kinase (JNK)-dependent Acute Liver Injury from Acetaminophen or Tumor Necrosis Factor (TNF) Requires Mitochondrial Sab Protein Expression in Mice

Abstract

Sustained JNK activation plays a critical role in hepatotoxicity by acetaminophen or GalN/TNF-␣. To address the importance of JNK translocation to mitochondria that accompanies sustained activation in these models, we assessed the importance of the expression of a potential initial target of JNK in the outer membrane of mitochondria, namely Sab (SH3 domain-binding protein that preferentially associates with Btk), also known as Sh3bp5 (SH3 domain-binding protein 5). Silencing the expression of Sab in the liver using adenoviral shRNA inhibited sustained JNK activation and mitochondrial targeting of JNK and the upstream MKK4 (MAPK kinase 4), accompanied by striking protection against liver injury in vivo and in cultured hepatocytes in both toxicity models. We conclude that mitochondrial Sab may serve as a platform for the MAPK pathway enzymes and that the interaction of stress-activated JNK with Sab is required for sustained JNK activation and toxicity.

Expressions of SH3BP5, LMO3, and SNAP25 in diffuse large B‐cell lymphoma cells and their association with clinical features

“…SH3BP5 also interacts with c‐Jun NH2‐terminal kinase (JNK) 19, which is required for survival and proliferation of B‐cell lymphoma cells 20, 21. The endogenous level of SH3BP5 positively regulates JNK 22, 23; however, the overexpressed SH3BP5 inhibits JNK 24. If SH3BP5 in DLBCL cells acts similarly as that in normal B cells, these findings suggest that SH3BP5 overexpression in DLBCL patients might be associated with a favorable prognosis.…”

Evaluation of Three-Dimensional Cultured HepG2 Cells in a Nano Culture Plate System: an In Vitro Human Model of Acetaminophen Hepatotoxicity

“…Mitochondrial protein adducts cause generation of reactive oxygen species in mitochondria to induce the activation of glycogen synthase kinase-3b (GSK-3b), mixed-lineage kinase-3 (MLK3), and apoptosis signal-regulating kinase-1 (ASK-1) (36). The early phase of JNK activation in APAP-induced hepatotoxicity most likely involves GSK-3b and MLK3, and the rate phase seems to involve ASK-1 through MAP Kinase Kinase (MKK) 4/7 activation (33,37). JNK phosphorylation amplified further mitochondrial damage and induced subsequent mitochondrial permeability transition (MPT).…”

Sensitivity of ovarian cancer cells to acetaminophen reveals biological pathways that affect patient survival

“…This finding suggests a clinical relevance of the identified molecular signaling pathways in OVCA. Acetaminophen hepatotoxicity is known to be mediated through the JNK pathway (17). Antineoplastic properties have been demonstrated in vitro, where acetaminophen has been shown to enhance the apoptotic effect of cisplatin and paclitaxel in SKOV3 human ovarian carcinoma cells through modulation of intracellular glutathione concentration (4).…”

“…However, the presence of JNK is required for development of gastric cancer, suggesting its role in carcinogenesis (23). The JNK pathway has previously been implicated in acetaminophen-induced hepatotoxicity (17). JNK expression has been shown in a substantial number of OVCA patients and its expression was correlated to progression-free survival, while inhibition of JNK resulted in decreased tumor growth in vivo (24).…”