Mutual dependence of Foxo3a and PGC-1alpha in the induction of oxidative stress genes.

Oxidative stress is a hallmark of metabolism-related diseases and a risk factor for atherosclerosis. FoxO factors have been shown to play a key role in vascular endothelial development and homeostasis. Foxo3a can protect quiescent cells from oxidative stress through the regulation of detoxification genes such as sod2 and catalase. Here we show that Foxo3a is a direct transcriptional regulator of a group of oxidative stress protection genes in vascular endothelial cells. Importantly, Foxo3a activity requires the transcriptional co-activator PGC-1α, because it is severely curtailed in PGC-1α-deficient endothelial cells. Foxo3a and PGC-1α appear to interact directly, as shown by co-immunoprecipitation and in vitro interaction assays, and are recruited to the same promoter regions. The notion that Foxo3a and PGC-1α interact directly to regulate oxidative stress protection genes in the vascular endothelium is supported by the observation that PGC-1α transcriptional activity at the sod2 (manganese superoxide dismutase) promoter requires a functional FoxO site. We also demonstrate that Foxo3a is a direct transcriptional regulator of PGC-1α, suggesting that an auto-regulatory cycle regulates Foxo3a/PGC-1α control of the oxidative stress response.

[1]  D. Sorescu,et al.  FOXO3A Regulates Peroxiredoxin III Expression in Human Cardiac Fibroblasts* , 2008, Journal of Biological Chemistry.

[2]  Tajpreet Kaur,et al.  Potential target sites to modulate vascular endothelial dysfunction: current perspectives and future directions. , 2008, Toxicology.

[3]  U. Landmesser,et al.  Endothelial Dysfunction as an Early Sign of Atherosclerosis , 2007, Herz Kardiovaskuläre Erkrankungen.

[4]  Q. Tong,et al.  SIRT2 deacetylates FOXO3a in response to oxidative stress and caloric restriction , 2007, Aging cell.

[5]  D. Tindall,et al.  Dynamic FoxO transcription factors , 2007, Journal of Cell Science.

[6]  M. Birnbaum,et al.  Akt/PKB regulates hepatic metabolism by directly inhibiting PGC-1α transcription coactivator , 2007, Nature.

[7]  J. Szustakowski,et al.  Estrogen-related receptor α is essential for the expression of antioxidant protection genes and mitochondrial function , 2007 .

[8]  Yonghong Xiao,et al.  FoxOs Are Lineage-Restricted Redundant Tumor Suppressors and Regulate Endothelial Cell Homeostasis , 2007, Cell.

[9]  M. Monsalve,et al.  Mitochondrial dysfunction in human pathologies. , 2007, Frontiers in bioscience : a journal and virtual library.

[10]  C. Block,et al.  Mechanisms linking obesity with cardiovascular disease , 2006, Nature.

[11]  Huiyun Liang,et al.  Staying Current PGC-1 : a key regulator of energy metabolism , 2006 .

[12]  S. Luquet,et al.  Thermoregulatory and metabolic defects in Huntington's disease transgenic mice implicate PGC-1alpha in Huntington's disease neurodegeneration. , 2006, Cell metabolism.

[13]  Jiandie D. Lin,et al.  PGC-1α protects skeletal muscle from atrophy by suppressing FoxO3 action and atrophy-specific gene transcription , 2006, Proceedings of the National Academy of Sciences.

[14]  Jiandie D. Lin,et al.  Suppression of Reactive Oxygen Species and Neurodegeneration by the PGC-1 Transcriptional Coactivators , 2006, Cell.

[15]  M. Monsalve,et al.  Nitric oxide regulates mitochondrial oxidative stress protection via the transcriptional coactivator PGC‐1α , 2006 .

[16]  R. DePinho,et al.  Involvement of Foxo transcription factors in angiogenesis and postnatal neovascularization. , 2005, The Journal of clinical investigation.

[17]  M. Monsalve,et al.  PGC-1α regulates the mitochondrial antioxidant defense system in vascular endothelial cells , 2005 .

[18]  S. Nemoto,et al.  SIRT1 Functionally Interacts with the Metabolic Regulator and Transcriptional Coactivator PGC-1α* , 2005, Journal of Biological Chemistry.

[19]  Michael D. Schneider,et al.  Energizer: PGC-1α keeps the heart going , 2005 .

[20]  P. Coffer,et al.  Induction of prosurvival molecules by apoptotic stimuli: involvement of FOXO3a and ROS , 2005, Oncogene.

[21]  K. Tryggvason,et al.  Distinctive functions of membrane type 1 matrix-metalloprotease (MT1-MMP or MMP-14) in lung and submandibular gland development are independent of its role in pro-MMP-2 activation. , 2005, Developmental biology.

[22]  J. Bos,et al.  FOXO transcription factor activation by oxidative stress mediated by the small GTPase Ral and JNK , 2004, The EMBO journal.

[23]  M. Daly,et al.  PGC-1α-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes , 2003, Nature Genetics.

[24]  N. Maulik.  Redox signaling of angiogenesis. , 2002, Antioxidants & redox signaling.

[25]  Geert J. P. L. Kops,et al.  Forkhead transcription factor FOXO3a protects quiescent cells from oxidative stress , 2002, Nature.

[26]  S. R. Datta,et al.  DNA Repair Pathway Stimulated by the Forkhead Transcription Factor FOXO3a Through the Gadd45 Protein , 2002, Science.

[27]  S. Nemoto,et al.  Redox Regulation of Forkhead Proteins Through a p66shc-Dependent Signaling Pathway , 2002, Science.

[28]  J. Lammers,et al.  Expression of the pro-apoptotic Bcl-2 family member Bim is regulated by the forkhead transcription factor FKHR-L1 , 2000, Current Biology.

[29]  P. Puigserver,et al.  Direct coupling of transcription and mRNA processing through the thermogenic coactivator PGC-1. , 2000, Molecular cell.

[30]  T. Finkel.  Redox‐dependent signal transduction , 2000, FEBS letters.

[31]  L. Peso,et al.  Regulation of the forkhead transcription factor FKHR, but not the PAX3-FKHR fusion protein, by the serine/threonine kinase Akt , 1999, Oncogene.

[32]  Guillaume Adelmant,et al.  Activation of PPARγ coactivator-1 through transcription factor docking , 1999 .

[33]  M. Freichel,et al.  Characterisation of explanted endothelial cells from mouse aorta: electrophysiology and Ca2+ signalling , 1999, Pflügers Archiv.

[34]  Y. Yazaki,et al.  Potential Role of Protein Kinase B in Insulin-induced Glucose Transport, Glycogen Synthesis, and Protein Synthesis* , 1998, The Journal of Biological Chemistry.

[35]  W. Cavenee,et al.  Cloning and characterization of three human forkhead genes that comprise an FKHR-like gene subfamily. , 1998, Genomics.

[36]  J. Redondo,et al.  Transcriptional up-regulation of intracellular adhesion molecule-1 in human endothelial cells by the antioxidant pyrrolidine dithiocarbamate involves the activation of activating protein-1. , 1996, Journal of immunology.

[37]  K R Spring,et al.  Uptake of fluorescent dyes associated with the functional expression of the cystic fibrosis transmembrane conductance regulator in epithelial cells. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[38]  P. Carlsson,et al.  Cloning and characterization of seven human forkhead proteins: binding site specificity and DNA bending. , 1994, The EMBO journal.

[39]  R. Weinberg,et al.  Tumor spectrum analysis in p53-mutant mice , 1994, Current Biology.