0000000000064432
AUTHOR
Angel R. Nebreda
Liver-specific p38α deficiency causes reduced cell growth and cytokinesis failure during chronic biliary cirrhosis in mice
p38α mitogen-activated protein kinases (MAPK) may be essential in the up-regulation of proinflammatory cytokines and can be activated by transforming growth factor β, tumor necrosis factor-α, interleukin-1β, and oxidative stress. p38 MAPK activation results in hepatocyte growth arrest, whereas increased proliferation has been considered a hallmark of p38α-deficient cells. Our aim was to assess the role of p38α in the progression of biliary cirrhosis induced by chronic cholestasis as an experimental model of chronic inflammation associated with hepatocyte proliferation, apoptosis, oxidative stress, and fibrogenesis. Cholestasis was induced in wildtype and liver-specific p38α knockout mice by…
p38 MAPK: A dual role in hepatocyte proliferation through reactive oxygen species
p38 MAPKs are important mediators of signal transduction that respond to a wide range of extracellular stressors such as UV radiation, osmotic shock, hypoxia, pro-inflammatory cytokines, and oxidative stress. The most abundant family member is p38α, which helps to couple cell proliferation and growth in response to certain damaging stimuli. In fact, increased proliferation and impaired differentiation are hallmarks of p38α-deficient cells. It has been reported that reactive oxygen species (ROS) play a critical role in cytokine-induced p38α activation. Under physiological conditions, p38α can function as a mediator of ROS signaling and either activate or suppress cell cycle progression depen…
p38α regulates actin cytoskeleton and cytokinesis in hepatocytes during development and aging.
[Background]: Hepatocyte poliploidization is an age-dependent process, being cytokinesis failure the main mechanism of polyploid hepatocyte formation. Our aim was to study the role of p38α MAPK in the regulation of actin cytoskeleton and cytokinesis in hepatocytes during development and aging. [Methods]: Wild type and p38α liver-specific knock out mice at different ages (after weaning, adults and old) were used. [Results]: We show that p38α MAPK deficiency induces actin disassembly upon aging and also cytokinesis failure leading to enhanced binucleation. Although the steady state levels of cyclin D1 in wild type and p38α knock out old livers remained unaffected, cyclin B1- a marker for G2/M…
Long term p38-a deficiency up-regulates antioxidant enzymes through compensatory NF-?B activation
p38a MAPK may function as a mediator of reactive oxygen species signaling and thus p38a is considered a sensor of oxidative stress. In liver-specific p38a knock-out (KO) adult mice we previously found glutathione depletion and down-regulation of antioxidant enzymes. Our aim was to assess the influence of long-term p38a deficiency on oxidative stress and on the regulation of antioxidant enzymes in liver of old mice. To this end, wild type or liver-specific KO mice after weaning, at 4-6 months of age, or at 24 months of age were used. Reduced glutathione (GSH) and oxidized glutathione levels were determined by mass spectrometry, gene expression of antioxidant enzymes was determined by RT-PCR,…
p38α MAPK is required for contact inhibition
Proliferation of nontransformed cells is regulated by cell-cell contacts, which are referred to as contact-inhibition. Despite its generally accepted importance for cell cycle control, knowledge about the intracellular signalling pathways involved in contact inhibition is scarce. In the present work we show that p38alpha mitogen-activated protein kinase (MAPK) is involved in the growth-inhibitory signalling cascade of contact inhibition in fibroblasts. p38alpha activity is increased in confluent cultures of human fibroblasts compared to proliferating cultures. Time course studies show a sustained activation of p38alpha in response to cell-cell contacts in contrast to a transient activation …
p38α and NF-κB regulate antioxidant defense in the liver through an age-dependent mechanism
p38α MAPK is a sensor of oxidative stress. The aim of this work was to assess the role of p38α in the regulation of the antioxidant defense in the liver with aging. Livers ofyoung and old wild type (WT) and p38α liver-specific knock out (KO) mice were used to determine glutathione redox status by mass spectrometry; malondialdehyde (MDA) levels by HPLC; mRNA expression of glutamate cysteine ligase (Gclc), Sod1, Sod2 and catalase by RT-PCR and nuclear levels of NF-κB subunit p65 by western-blotting. Chromatin immunoprecipitation (ChIP) assay of p65 was performed. Young KO liver exhibited increased in GSSG/GSH ratio and MDA levels when are compared with young WT mice. However, old KO mice had …
Age-dependent regulation of antioxidant genes by p38α MAPK in the liver
p38α is a redox sensitive MAPK activated by pro-inflammatory cytokines and environmental, genotoxic and endoplasmic reticulum stresses. The aim of this work was to assess whether p38α controls the antioxidant defense in the liver, and if so, to elucidate the mechanism(s) involved and the age-related changes. For this purpose, we used liver-specific p38α-deficient mice at two different ages: young-mice (4 months-old) and old-mice (24 months-old). The liver of young p38α knock-out mice exhibited a decrease in GSH levels and an increase in GSSG/GSH ratio and malondialdehyde levels. However, old mice deficient in p38α had higher hepatic GSH levels and lower GSSG/GSH ratio than young p38α knock-…