The MAP kinase phosphatase-1 MKP-1/DUSP1 is a regulator of human liver response to transplantation.
Orthotopic liver transplantation (OLT) continues to be the only remedy for end-stage liver disease. In an attempt to decrease the ever-widening gap between organ donor and recipient numbers, and ultimately make more livers amenable to transplantation, we characterized the healthy human liver's response to ischemia and reperfusion-induced injury during transplantation. This was carried out by transcriptional profiling using cDNA microarray to identify genes whose expression was modulated at the 1-h postreperfusion time point. We observed that the map kinase phosphatase-1/dual-specificity phosphatase-1 (MKP-1/DUSP1) mRNA was strongly and significantly upregulated. Validation of this observation was carried out using reverse transcriptase-polymerase chain reaction (RT-PCR), immunoblotting and immunohistochemistry. In addition, we characterized the signaling pathways regulating MKP-1 expression using the human hepatoma cell line HepG2. Finally, by combining MKP-1 silencing with reperfusion-associated stresses, we reveal the preferential role of this protein in attenuating the activity of the JNK and p38(MAPK) pathways, and the resulting apoptosis, making MKP-1 a potential target for therapeutic intervention.
Boutros
T
T
Organelle Signalling Laboratory, Department of Surgery, McGill University, Montreal, QC, Canada.
Nantel
A
A
Emadali
A
A
Tzimas
G
G
Conzen
S
S
Chevet
E
E
Metrakos
P P
PP
D017209:Apoptosis / Q000502:physiology; D001706:Biopsy; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D054638:Dual Specificity Phosphatase 1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology; D016031:Liver Transplantation / Q000502:physiology*; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000378:metabolism; D015427:Reperfusion Injury / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D015398:Signal Transduction / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D012333:RNA, Messenger; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; C517019:DUSP1 protein, human; D054638:Dual Specificity Phosphatase 1