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      Mouse Hepatic Oval Cells Require Met-Dependent PI3K to Impair TGF-β-Induced Oxidative Stress and Apoptosis

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          Abstract

          We have previously shown that oval cells harboring a genetically inactivated Met tyrosine kinase (Met −/− oval cells) are more sensitive to TGF-β-induced apoptosis than cells expressing a functional Met (Met flx/flx), demonstrating that the HGF/Met axis plays a pivotal role in oval cell survival. Here, we have examined the mechanism behind this effect and have found that TGF-β induced a mitochondria-dependent apoptotic cell death in Met flx/flx and Met −/− oval cells, associated with a marked increase in levels of the BH3-only proteins Bim and Bmf. Bmf plays a key role during TGF-β-mediated apoptosis since knocking down of BMF significantly diminished the apoptotic response in Met −/− oval cells. TGF-β also induced oxidative stress accompanied by NADPH oxidase 4 (Nox4) mRNA up-regulation and decreased protein levels of antioxidant enzymes. Antioxidants inhibit both TGF-β-induced caspase 3 activity and Bmf up-regulation, revealing an oxidative stress-dependent Bmf regulation by TGF-β. Notably, oxidative stress-related events were strongly amplified in Met −/− oval cells, emphasizing the critical role of Met in promoting survival. Pharmacological inhibition of PI3K did impair HGF-driven protection from TGF-β-induced apoptosis and increased sensitivity of Met flx/flx oval cells to TGF-ß by enhancing oxidative stress, reaching apoptotic indices similar to those obtained in Met −/− oval cells. Interestingly, both PI3K inhibition and/or knockdown itself resulted in caspase-3 activation and loss of viability in Met flx/flx oval cells, whereas no effect was observed in Met −/− oval cells. Altogether, results presented here provide solid evidences that both paracrine and autocrine HGF/Met signaling requires PI3K to promote mouse hepatic oval cell survival against TGF-β-induced oxidative stress and apoptosis.

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          Most cited references63

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          TGFbeta-SMAD signal transduction: molecular specificity and functional flexibility.

          Ligands of the transforming growth factor-beta (TGFbeta) superfamily of growth factors initiate signal transduction through a bewildering complexity of ligand-receptor interactions. Signalling then converges to nuclear accumulation of transcriptionally active SMAD complexes and gives rise to a plethora of specific functional responses in both embryos and adult organisms. Current research is focused on the mechanisms that regulate SMAD activity to evoke cell-type-specific and context-dependent transcriptional programmes. An equally important challenge is understanding the functional role of signal strength and duration. How are these quantitative aspects of the extracellular signal regulated? How are they then sensed and interpreted, and how do they affect responses?
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            Scatter factor/hepatocyte growth factor is essential for liver development.

            Polypeptide growth factors are important effectors of cell growth and differentiation in vitro and are thought to be critical for processes such as specification of cell fate, tissue growth and organogenesis in vivo. Scatter factor/hepatocyte growth factor (SF/HGF) is the prototype of an emerging family of growth factors that resemble in their domain structure and mechanism of activation the blood proteinase plasminogen. The cellular responses of SF/HGF are mediated by the c-Met tyrosine kinase receptor. Here we report that mice lacking SF/HGF fail to complete development and die in utero. The mutation affects the embryonic liver, which is reduced in size and shows extensive loss of parenchymal cells. In addition, development of the placenta, particularly of trophoblast cells, is impaired. Thus, SF/HGF is essential for the development of several epithelial organs.
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              Hepatocyte growth factor/c-met signaling pathway is required for efficient liver regeneration and repair.

              Hepatocyte growth factor/scatter factor c-met signaling pathway is of central importance during development as well as in tumorigenesis. Because homozygous null mice for either hgf/sf or c-met die in utero, we used Cre/loxP-mediated gene targeting to investigate the function of c-met specifically in the adult liver. Loss of c-met appeared not to be detrimental to hepatocyte function under physiological conditions. Nonetheless, the adaptive responses of the liver to injury were dramatically affected. Mice lacking c-met gene in hepatocytes were hypersensitive to Fas-induced apoptosis. When injected with a low dose of anti-Fas antibody, the majority of these mice died from massive apoptosis and hemorrhagic necrosis, whereas all wild-type mice survived with signs of minor injury. After a challenge with a single necrogenic dose of CCl4, c-met conditional knockout mice exhibited impaired recovery from centrolobular lesions rather than a deficit in hepatocyte proliferation. The delayed healing was associated with a persistent inflammatory reaction, over-production of osteopontin, early and prominent dystrophic calcification, and impaired hepatocyte scattering/migration into diseased areas. These studies provide direct genetic evidence in support of the critical role of c-met in efficient liver regeneration and suggest that disruption of c-met affects primarily hepatocyte survival and tissue remodeling.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2013
                2 January 2013
                : 8
                : 1
                : e53108
                Affiliations
                [1 ]Dep. Bioquímica y Biología Molecular II, Facultad de Farmacia, Universidad Complutense, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain
                [2 ]Laboratori d´Oncologia Molecular and Departament de Ciències Fisiològiques II, Universitat de Barcelona, Institut d´Investigació Biomèdica de Bellvitge, ĹHospitalet de Llobregat, Barcelona, Spain
                Osaka University Graduate School of Medicine, Japan
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: MF CR IF BH AS. Performed the experiments: AMP GC ASC MGA DMF. Analyzed the data: AMP GC ASC MGA DMF MF CR IF BH AS. Wrote the paper: BH AS.

                [¤a]

                Current address: Instituto de Investigaciones Biomédicas “Alberto Sols”, Madrid, Spain

                [¤b]

                Current address: Universidad de Cartagena, Cartagena de Indias, Colombia

                ¶ These authors are joint senior authors on this work.

                Article
                PONE-D-12-22164
                10.1371/journal.pone.0053108
                3534654
                23301029
                e7835d85-229d-48f3-a321-3725d118a51e
                Copyright @ 2013

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 25 July 2012
                : 23 November 2012
                Page count
                Pages: 14
                Funding
                AMP was recipient of a research-training contract (grant SAF2006-12025) from the Ministry of Education and Science. GC was recipient of a research-training contract from the Ministry of Education and Science. ASC was recipient of an Alban scholarship program and then a research assistant contract (grant SAF2009-12477). MGA is recipient of a research assistant contract (grant S2010/BMD-2402). This work has been supported by grants SAF2006-12025 from Ministry of Education and Science (Spain), SAF2009-12477 from Ministry of Science and Innovation (Spain), and 920359 (CAM-UCM, BSCH-UCM). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology
                Model Organisms
                Animal Models
                Mouse
                Molecular Cell Biology
                Cellular Types
                Stem Cells
                Adult Stem Cells
                Signal Transduction
                Signaling Cascades
                Apoptotic Signaling Cascade
                TGF-beta signaling cascade
                Signaling in Cellular Processes
                Antiapoptotic Signaling
                Apoptotic Signaling
                Signaling Pathways
                Autocrine Signaling
                Cell Death

                Uncategorized
                Uncategorized

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