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  • The EMBO Journal (2001) 20, 6712 - 6723
  • doi:10.1093/emboj/20.23.6712

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

Martina Buck1,2, Lian Zhang2,3, Nicholas A. Halasz3,4, Tony Hunter1 and Mario Chojkier2,3,5

  1. Molecular and Cell Biology Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA
  2. Department of Medicine, University of California, La Jolla, CA 92037, USA
  3. Department of VA Medical Center, San Diego, CA 92161, USA
  4. Department of Surgery, University of California, La Jolla, CA 92037, USA
  5. Department of Center for Molecular Genetics, University of California, La Jolla, CA 92037, USA

Correspondence to:

Martina Buck, E-mail: mbuck@vapop.ucsd.edu

Received 1 May 2001; Accepted 12 October 2001; Revised 27 September 2001

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-alpha (TNF-alpha) treatment of primary mouse hepatocytes or TNF-alpha overexpression in a mouse model of cachexia induces oxidative stress, nitric oxide synthase (NOS) expression and phosphorylation of C/EBPbeta 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-alpha effects on hepatocytes. We found similar molecular abnormalities in the liver of patients with cancer-cachexia. The cytoplasmic localization and association of C/EBPbeta-PSer239 with CRM1 (exportin-1) in TNF-alpha-treated hepatocytes was inhibited by leptomycin B, a blocker of CRM1 activity. Hepatic cells expressing the non-phosphorylatable C/EBPbeta alanine mutant were refractory to the inhibitory effects of TNF-alpha on albumin transcription since the mutant remained localized to the nucleus. Treatment of TNF-alpha mice with antioxidants or NOS inhibitors prevented phosphorylation of C/EBPbeta on Ser239 and its nuclear export, and rescued the abnormal albumin gene expression.

  • Keywords:

    • AIDS,
    • albumin,
    • cancer,
    • NOS,
    • oxidative stress