Decreased albumin expression is a frequent feature of cachexia patients afflicted with chronic diseases, including cancer, and a major contributor to their morbidity. Here we show that tumor necrosis-α (TNF-α) treatment of primary mouse hepatocytes or TNF-α overexpression in a mouse model of cachexia induces oxidative stress, nitric oxide synthase (NOS) expression and phosphorylation of C/EBPβ on Ser239, within the nuclear localization signal, thus inducing its nuclear export, which inhibits transcription from the albumin gene. SIN-1, a NO donor, duplicated the TNF-α effects on hepatocytes. We found similar molecular abnormalities in the liver of patients with cancer-cachexia. The cytoplasmic localization and association of C/EBPβ-PSer239 with CRM1 (exportin-1) in TNF-α-treated hepatocytes was inhibited by leptomycin B, a blocker of CRM1 activity. Hepatic cells expressing the non-phosphorylatable C/EBPβ alanine mutant were refractory to the inhibitory effects of TNF-α on albumin transcription since the mutant remained localized to the nucleus. Treatment of TNF-α mice with antioxidants or NOS inhibitors prevented phosphorylation of C/EBPβ on Ser239 and its nuclear export, and rescued the abnormal albumin gene expression
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