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J. Biol. Chem. 278 (46): 45485-45491

© 2003 by The American Society for Biochemistry and Molecular Biology, Inc.

Convergence of Peroxisome Proliferator-activated Receptor {gamma} and Foxo1 Signaling Pathways*

Paul Dowell{ddagger}§, Tamara C. Otto{ddagger}, Saleh Adi¶, , and M. Daniel Lane{ddagger}

{ddagger}Biological Chemistry and Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205

Abstract: The forkhead factor Foxo1 (or FKHR) was identified in a yeast two-hybrid screen as a peroxisome proliferator-activated receptor (PPAR) {gamma}-interacting protein. Foxo1 antagonized PPAR{gamma} activity and vice versa indicating that these transcription factors functionally interact in a reciprocal antagonistic manner. One mechanism by which Foxo1 antagonizes PPAR{gamma} activity is through disruption of DNA binding as Foxo1 inhibited the DNA binding activity of a PPAR{gamma}/retinoid X receptor {alpha} heterodimeric complex. The Caenorhabditis elegans nuclear hormone receptor, DAF-12, interacted with the C. elegans forkhead factor, DAF-16, paralleling the interaction between PPAR{gamma} and Foxo1. daf-12 and daf-16 have been implicated in C. elegans insulin-like signaling pathways, and PPAR{gamma} and Foxo1 likewise have been linked to mammalian insulin signaling pathways. These results suggest a convergence of PPAR{gamma} and Foxo1 signaling that may play a role in insulin action and the insulinomimetic properties of PPAR{gamma} ligands. A more general convergence of nuclear hormone receptor and forkhead factor pathways may be important for multiple biological processes and this convergence may be evolutionarily conserved.

Received for publication August 15, 2003.

* This work was supported by Grants DK09894 and DK64934 (to P. D.) and DK38418 (to M. D. L.) from NIDDK, National Institutes of Health and by an Institutional Research Grant from Johns Hopkins University (to S. A.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ To whom correspondence should be addressed: Dept. of Biological Chemistry, WBSB 509, 725 N. Wolfe St., Baltimore, MD 21205. Tel.: 410-955-3975; Fax: 410-955-0903; E-mail: dowellp{at}jhmi.edu.

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