Convergence of peroxisome proliferator-activated receptor gamma and Foxo1 signaling pathways.
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 PPARgamma activity and vice versa indicating that these transcription factors functionally interact in a reciprocal antagonistic manner. One mechanism by which Foxo1 antagonizes PPARgamma activity is through disruption of DNA binding as Foxo1 inhibited the DNA binding activity of a PPARgamma/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 PPARgamma and Foxo1. daf-12 and daf-16 have been implicated in C. elegans insulin-like signaling pathways, and PPARgamma and Foxo1 likewise have been linked to mammalian insulin signaling pathways. These results suggest a convergence of PPARgamma and Foxo1 signaling that may play a role in insulin action and the insulinomimetic properties of PPARgamma 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.
Dowell
Paul
P
Biological Chemistry and Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. dowellp@jhmi.edu
Otto
Tamara C
TC
Adi
Saleh
S
Lane
M Daniel
MD
D041721:3T3-L1 Cells; D000818:Animals; D015153:Blotting, Western; D017173:Caenorhabditis elegans; D029742:Caenorhabditis elegans Proteins; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D019281:Dimerization; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism; D008024:Ligands; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D010957:Plasmids / Q000378:metabolism; D011485:Protein Binding; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection; D020798:Two-Hybrid System Techniques
D029742:Caenorhabditis elegans Proteins; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D007328:Insulin; D008024:Ligands; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; C108831:daf-16 protein, C elegans; D004247:DNA; D008156:Luciferases; D005982:Glutathione Transferase