Chapter 10 Forkhead proteins and the regulation of hepatic gene expression

The FoxO proteins belong to a subfamily of forkhead transcription factors, which all have the so-called 'winged-helix' like DNA-binding structure in common. The FoxO-proteins in mammals are homologues of Daf-16 in Caenorrhabditis elegans. Based on genetic studies, Daf-16 was initially identified as a factor that is involved in the regulation of the life span of the organism and that is regulated by an insulin-like signaling cascade in C. elegans. In mammals, three major insulin-regulated Daf-16 homologues FoxO-family transcription factors have been identified so far: FoxO1 (FKHR), FoxO3a (FKHRL1), and FoxO4 (AFX). In addition to the N-terminal 'winged-helix-domain', these three FoxO-proteins share several structural and functional characteristics. All of them have a C-terminal transactivation domain, a nuclear localization signal (NLS), a nuclear exclusion sequence (NES), and three RxRxxS/T consensus sites for phosphorylation by protein kinase B (PKB), a serine-/threonine kinase, which is activated after stimulation of cells with insulin and other growth factors. Phosphorylation of FoxO-proteins by PKB results in transcriptional inactivation and nuclear exclusion. Initially, the FoxO-transcription factors were thought to bind to the so-called insulin-responsive structures (IRS; (C/G)(A/T)AAA(C/A)A) that are typically present in the promoters of several insulin-regulated genes playing an important role in fuel metabolism, e.g. the phosphoenolpyruvate carboxykinase (PEPCK) and the glucose-6-phosphatase catalytic subunit (G6 Pase). However, FoxO-proteins have pleiotropic biological functions serving as a crossroad to a variety of signaling pathways. Here, we will summarize the role of FoxO-proteins in hepatic gene expression and metabolism.