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  • 1
    Keywords: RECEPTOR ; EXPRESSION ; GROWTH ; GROWTH-FACTOR ; proliferation ; tumor ; FACTOR RECEPTOR ; INHIBITION ; MODEL ; PATHWAY ; PATHWAYS ; DISEASE ; liver ; GENE ; GENES ; transcription ; MICE ; TUMOR-NECROSIS-FACTOR ; DOWN-REGULATION ; GROWTH-FACTOR RECEPTOR ; ALPHA ; ACID ; MOUSE ; resistance ; INDUCED APOPTOSIS ; UP-REGULATION ; NECROSIS-FACTOR-ALPHA ; inactivation ; DAMAGE ; SIGNALING PATHWAY ; SIGNALING PATHWAYS ; PHENOTYPE ; MOUSE MODEL ; INJURY ; EPIDERMAL-GROWTH-FACTOR ; INCREASED EXPRESSION ; signaling ; CYTOKINE ; FAS ; BILE ; INTERLEUKIN-6 ; KNOCKOUT MICE ; methods ; BARRIER ; NECROSIS ; Stat3 ; CHOLESTASIS ; interleukin 6 ; FACTOR-RECEPTOR ; Conditional mouse model ; BILE-ACIDS ; PRIMARY HEPATOCYTES
    Abstract: BACKGROUND & AIMS: Signal transducer and activator of transcription 3 (Stat3) is the main mediator of interleukin-6-type cytokine signaling required for hepatocyte proliferation and hepatoprotection, but its role in sclerosing cholangitis and other cholestatic liver diseases remains unresolved. METHODS: We investigated the role of Stat3 in inflammation-induced cholestatic liver injury and used mice lacking the multidrug resistance gene 2 (mdr2(-/-)) as a model for SC. RESULTS: We show that conditional inactivation of Stat3 in hepatocytes and cholangiocytes (stat3(Delta hc)) of mdr2(-/-) mice strongly aggravated bile acid-induced liver injury and fibrosis. A similar phenotype was observed in mdr2(-/-) mice lacking interleukin-6 production. Biochemical and molecular characterization suggested that Stat3 exerts hepatoprotective functions in both hepatocytes and cholangiocytes. Loss of Stat3 led to increased expression of tumor necrosis factor alpha, which might reduce the barrier function of bile ducts. Moreover, Stat3-deficient hepatocytes displayed up-regulation of bile acid biosynthesis genes and down-regulation of hepatoprotective epidermal growth factor receptor and insulin-like growth factor 1 signaling pathways. Consistently, stat3(Delta hc) mice were more sensitive to cholic acid-induced liver damage than control mice. CONCLUSIONS: Our data suggest that Stat3 prevents cholestasis and liver damage in sclerosing cholangitis via regulation of pivotal functions in hepatocytes and cholangiocytes
    Type of Publication: Journal article published
    PubMed ID: 20193684
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  • 2
    Keywords: brain ; EXPRESSION ; Germany ; MODEL ; SYSTEM ; DISEASE ; GENE ; GENES ; GENOME ; HYBRIDIZATION ; PROTEIN ; RNA ; SACCHAROMYCES-CEREVISIAE ; MECHANISM ; FAMILY ; IMPACT ; BIOLOGY ; chromosome ; FREQUENCY ; GENOMEWIDE SCREEN ; FREQUENCIES ; hippocampus ; MOUSE ; IN-SITU ; MUTATION ; etiology ; MUTATIONS ; PERVASIVE DEVELOPMENTAL DISORDERS ; INVOLVEMENT ; INDIVIDUALS ; in situ hybridization ; FAMILIES ; TRANSLATION ; MISSENSE MUTATION ; autism ; function ; Male ; SPECTRUM ; SUBSTITUTION ; AMINO-ACID SUBSTITUTIONS ; autistic disorder ; PROTEIN GENE ; ribosomal protein ; SEROTONIN TRANSPORTER 5-HTT ; SUBUNIT PROTEIN ; X MENTAL-RETARDATION ; Xq28
    Abstract: Autism has a strong genetic background with a higher frequency of affected males suggesting involvement of X-linked genes and possibly also other factors causing the unbalanced sex ratio in the etiology of the disorder. We have identified two missense mutations in the ribosomal protein gene RPL10 located in Xq28 in two independent families with autism. We have obtained evidence that the amino-acid substitutions L206M and H213Q at the C-terminal end of RPL10 confer hypomorphism with respect to the regulation of the translation process while keeping the basic translation functions intact. This suggests the contribution of a novel, possibly modulating aberrant cellular function operative in autism. Previously, we detected high expression of RPL10 by RNA in situ hybridization in mouse hippocampus, a constituent of the brain limbic system known to be afflicted in autism. Based on these findings, we present a model for autistic disorder where a change in translational function is suggested to impact on those cognitive functions that are mediated through the limbic system
    Type of Publication: Journal article published
    PubMed ID: 16940977
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