Protein-tyrosine Phosphatase 1B Deficiency Protects against Fas-induced Hepatic Failure
| Autor: | Alan Cheng, Nadia Dubé, Veena Sangwan, Grigorios N. Paliouras, Michel L. Tremblay, Morag Park |
|---|---|
| Rok vydání: | 2006 |
| Předmět: |
medicine.medical_specialty
Fas Ligand Protein Phosphatase Apoptosis Stimulation Thymus Gland Protein tyrosine phosphatase Biology Biochemistry Antibodies Mice Internal medicine medicine Animals fas Receptor Phosphorylation Extracellular Signal-Regulated MAP Kinases Molecular Biology Protein Tyrosine Phosphatase Non-Receptor Type 1 Mice Inbred BALB C Membrane Glycoproteins Tumor Necrosis Factor-alpha NF-kappa B Cell Biology Fas receptor Cytoprotection Mice Mutant Strains Cell biology Endocrinology Liver Caspases Tumor Necrosis Factors Hepatocytes Female Hepatocyte growth factor Protein Tyrosine Phosphatases Liver Failure hormones hormone substitutes and hormone antagonists Signal Transduction medicine.drug |
| Zdroj: | Journal of Biological Chemistry. 281:221-228 |
| ISSN: | 0021-9258 |
| Popis: | Genetic disruption of protein-tyrosine phosphatase 1B (PTP1B) in mice leads to increased insulin sensitivity and resistance to weight gain. Although PTP1B has been implicated as a regulator of multiple signals, its function in other physiological responses in vivo is poorly understood. Here we demonstrate that PTP1B-null mice are resistant to Fas-induced liver damage and lethality, as evident by reduced hepatic apoptosis in PTP1B-null versus wild type mice and reduced levels of circulating liver enzymes. Activation of pro-apoptotic caspases-8, -9, -3, and -6 was attenuated in livers from PTP1B-null mice following Fas receptor stimulation, although components of the death-inducing signaling complex were intact. Activation of anti-apoptotic regulators, such as the hepatocyte growth factor/Met receptor tyrosine kinase, as well as Raf, ERK1/2, FLIP(L), and the NF-kappaB pathway, was elevated in response to Fas activation in livers from PTP1B-null mice. Using PTP1B-deficient primary hepatocytes, we show that resistance to Fas-mediated apoptosis is cell autonomous and that signals involving the Met, ERK1/2, and NF-kappaB pathways are required for cytoprotection. This study identifies a previously unknown physiological role for PTP1B in Fas-mediated liver damage and points to PTP1B as a potential therapeutic target against hepatotoxic agents. |
| Databáze: | OpenAIRE |
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