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Apoptosis in β‐catenin knockout mice occurs through the Fas pathway
Author(s) -
NejakBowen Kari Nichole,
Tan Xinping,
Dai Chunsun,
Monga Satdarshan
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.565.10
Subject(s) - apoptosis , fas ligand , tunel assay , fas receptor , knockout mouse , endocrinology , medicine , programmed cell death , chemistry , catenin , caspase 8 , gene knockout , signal transduction , caspase , biology , microbiology and biotechnology , wnt signaling pathway , receptor , gene , biochemistry
Suppression of β‐catenin signaling in developing and regenerating hepatocytes causes a basal increase in apoptosis through unknown mechanisms. Also, HGF is known to induce apoptosis through Met‐Fas dissociation. Here, we demonstrate that loss of β‐catenin also exacerbates Fas‐mediated apoptosis. Analysis of mRNA expression levels in wild‐type (WT) and β‐catenin knockout (KO) mice reveals a 9‐fold increase in HGF expression in KO, as determined by gene array; while, baseline levels of Met protein are decreased in KO compared to WT. Expression of Fas protein is unchanged between WT and KO under unstimulated conditions. Mice injected with Jo‐2 antibody (an agonist of the Fas pathway) were monitored for morbidity and examined morphologically and histologically upon sacrifice. KO mice show a dramatic increase in liver injury and a decreased survival upon Jo‐2 administration as compared to their WT counterparts, with extensive loss of architecture and hepatocyte apoptosis, as confirmed by TUNEL staining. Active caspase‐3 is also increased in KO compared to WT after Jo‐2 administration. Thus we have identified increased susceptibility of β‐catenin KO mice to Fas‐mediated cell death, which appears to be due to increased HGF, which might impact Met‐Fas stability and contribute to apoptosis.