title: FOXO1 stimulates ceruloplasmin promoter activity in human hepatoma cells treated with IL-6.
abstract: FOXO1, a member of the winged-helix family of transcription factors, is a ubiquitously expressed protein involved in regulating a variety of cellular processes including glucose homeostasis, apoptosis, cell cycle control, muscle differentiation, and angiogenesis. In addition to these biological functions, FOXO1 is a key player in the oxidative stress response by stimulating the expression of metal-containing anti-oxidant proteins such as manganese superoxide dismutase, selenoprotein P, and catalase. Evidence in the literature suggests that FOXO1 may also be capable of regulating the expression of the anti-oxidant protein Ceruloplasmin (Cp), a six-copper-containing protein synthesized and secreted mainly by the liver. In the present report, we demonstrate that FOXO1 stimulates Cp promoter activity in conjunction with the cytokine IL-6. Through deletional analysis and in vitro binding studies, we determine the DNA sequence responsible for the FOXO1-dependent regulation of the Cp proximal promoter. Finally, we demonstrate that FOXO1 is capable of enhancing the expression of endogenous Cp in human hepatic carcinoma cells treated with IL-6. These results allow us to identify FOXO1 as a regulator of Cp expression to promote the anti-oxidant pathway in response to IL-6 signaling.
authors.affiliation: Department of Genetics, Louisiana State University Health Sciences Center, 533 Bolivar Street, CSRB 6th floor, New Orleans, LA 70112, USA.
authors.forename: Alpa
authors.initials: A
authors.lastname: Sidhu
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Miller
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Hollenbach
mesh_terms: D045744:Cell Line, Tumor; D002570:Ceruloplasmin / Q000235:genetics*; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism* / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000187:drug effects; D015398:Signal Transduction
chemical_list: C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D015850:Interleukin-6; D002570:Ceruloplasmin