Nuclear export of phosphorylated C/EBPbeta mediates the inhibition of albumin expression by TNF-alpha

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Abstract
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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