In hepatocytes,

cell division is complex, because polyploidy and aneuploidy are extremely high in p53+/+ livers from mice3 and humans.4 Nonetheless, disruption of normal Aurka and Lats2—and to a lesser extent Foxm1 and Plk4—expression partially accounts for enrichment in mitotic segregation errors and enhanced polyploidy MAPK Inhibitor Library solubility dmso seen in p53-deficient liver. After PH, transcriptional activity of p53 and how it contributes to activation or repression of mitotic or cell cycle regulators is more difficult to interpret. There may be a partial compensation by TA-p73, which has been shown to play a role in liver tumor suppression in combination with p53.35 A fully delineated story of how hepatocytes survive, and even thrive, in spite of high levels of polyploidy and

aneuploidy is not yet clear. p53 and its downstream effectors contribute to polyploidization and mitotic fidelity, as shown here in vivo. Whether p53 regulation is connected to activation of the insulin receptor and AKT signaling, implicated in cytokinesis failure see more and formation of polyploid hepatic cells,36 is unknown. Further characterization of new hepato-specific cell cycle pathways and definition of regulatory mechanisms are critical to understanding development, homeostasis, regeneration, and pathology of the liver. Additional Supporting Information may be found in the online version of this article. “
“JNK plays science a key role in hepatotoxicity by binding and phos-phorylating Sab on the outer mitochondrial membrane (J Biol Chem 286, 35071-8, 2011, Cell Death Dis; 5:e989, Jan 9, 2014). The mechanism for how this event on the cytoplasmic face of the outer membrane leads to impaired mitochondrial electron transport, increased ROS, and APAP-induced necrosis is unknown. We focused our attention on dysregulation of tyro-sine kinases (Src) because mitochondrial Src activity is known to regulate multiple steps in electron transport in other contexts (Biochem J. 447, 281-9,2012). Methods: Isolated mouse liver mitochondria were exposed to pure activated JNK +/− ATP, with or without Src or protein tyrosine

phosphatase (Ptp) inhibitors. APAP (300mg/kg) or PBS was given by ip injection to C57BL/6N mice; mitochondria and cytoplasm were prepared at 1,2,4 hours and histology and serum ALT were assessed at 24 hours. Knockdown of target genes in liver was by adeno-shRNA. Results: Using resistance to proteinase K digestion, we identified intramitochondrial c-Src mainly in an activated form (P-419-c-Src). Upon exposure of isolated mitochondria to P-JNK plus ATP, P-c-Src levels markedly decreased while total c-Src was unchanged. The decrease of P-c-Src was accompanied by inhibition of oxygen consumption rate (OCR), which depended on Sab expression. Addition of Src inhibitors (PP2 or Src inhibitor 1) to normal mitochondria directly inhibited OCR.