Inactivation of the deubiquitinase CYLD in hepatocytes causes apoptosis, inflammation, fibrosis, and cancer.
The tumor suppressor cylindromatosis (CYLD) inhibits the NFκB and mitogen-activated protein kinase (MAPK) activation pathways by deubiquitinating upstream regulatory factors. Here we show that liver-specific disruption of CYLD triggers hepatocyte cell death in the periportal area via spontaneous and chronic activation of TGF-β activated kinase 1 (TAK1) and c-Jun N-terminal kinase (JNK). This is followed by hepatic stellate cell and Kupffer cell activation, which promotes progressive fibrosis, inflammation, tumor necrosis factor (TNF) production, and expansion of hepatocyte apoptosis toward the central veins. At later stages, compensatory proliferation results in the development of cancer foci featuring re-expression of oncofetal hepatic and stem cell-specific genes. The results demonstrate that, in the liver, CYLD acts as an important regulator of hepatocyte homeostasis, protecting cells from spontaneous apoptosis by preventing uncontrolled TAK1 and JNK activation.
Biomedical Sciences Research Center Alexander Fleming, 16672 Vari, Greece.
Kostas
K
Nikolaou
Ageliki
A
Tsagaratou
Christina
C
Eftychi
George
G
Kollias
George
G
Mosialos
Iannis
I
Talianidis
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D015153:Blotting, Western; D055028:Comparative Genomic Hybridization; D003546:Cysteine Endopeptidases / Q000235:genetics* / Q000378:metabolism; D000074749:Deubiquitinating Enzyme CYLD; D004789:Enzyme Activation / Q000187:drug effects; D005355:Fibrosis / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D022781:Hepatocytes / Q000378:metabolism* / Q000473:pathology; D007150:Immunohistochemistry; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D000099151:MAP Kinase Kinase Kinase 7
D003546:Cysteine Endopeptidases; D000074749:Deubiquitinating Enzyme CYLD; D048031:JNK Mitogen-Activated Protein Kinases; D020930:MAP Kinase Kinase Kinases; D014409:Tumor Necrosis Factor-alpha; D025521:Tumor Suppressor Proteins; D000099151:MAP Kinase Kinase Kinase 7; C511601:CYLD protein, mouse