The Forkhead Transcription Factor FOXO4 Induces the Down-regulation of Hypoxia-inducible Factor 1α by a von Hippel-Lindau Protein-independent Mechanism

Abstract

Tumors utilize hyperactivation of the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway to cope with deleterious environmental conditions. Activation of the PI3K/AKT pathway has been shown to increase protein expression of the α subunit of the hypoxia-inducible factor (HIF) 1, a key regulator of oxygen homeostasis. Elevated levels of HIF-1α induce expression of genes with critical roles in angiogenesis, erythropoiesis, and glucose metabolism, processes that are essential for tumor expansion. Here we examine the involvement of FOXO4 (also known as AFX), a member of the forkhead transcription factor superfamily that is negatively regulated by the PI3K/AKT pathway, in the regulation of HIF-1α protein expression. Nuclear expression of FOXO4 results in the suppression of various responses to hypoxia, including decreased vascular endothelial growth factor, glucose transporter 1, and erythropoietin expression. Interestingly, FOXO4 down-regulates the HIF-1α protein levels, consistent with the lack of hypoxia responsiveness. Previous results have revealed a role for prolyl hydroxylation and resultant von Hippel-Lindau protein (pVHL) interactions in the ubiquitinproteasome-mediated degradation of HIF-1α. However, neither inhibition of prolyl hydroxylases nor mutation of HIF-1α-hydroxylated prolines involved with pVHL-mediated binding inhibits the observed FOXO4-mediated down-regulation of HIF-1α. These results suggest a novel alternate mechanism for hypoxic regulation that is dependent upon the level of activation of FOXO4-mediated transcription. Tumors utilize hyperactivation of the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway to cope with deleterious environmental conditions. Activation of the PI3K/AKT pathway has been shown to increase protein expression of the α subunit of the hypoxia-inducible factor (HIF) 1, a key regulator of oxygen homeostasis. Elevated levels of HIF-1α induce expression of genes with critical roles in angiogenesis, erythropoiesis, and glucose metabolism, processes that are essential for tumor expansion. Here we examine the involvement of FOXO4 (also known as AFX), a member of the forkhead transcription factor superfamily that is negatively regulated by the PI3K/AKT pathway, in the regulation of HIF-1α protein expression. Nuclear expression of FOXO4 results in the suppression of various responses to hypoxia, including decreased vascular endothelial growth factor, glucose transporter 1, and erythropoietin expression. Interestingly, FOXO4 down-regulates the HIF-1α protein levels, consistent with the lack of hypoxia responsiveness. Previous results have revealed a role for prolyl hydroxylation and resultant von Hippel-Lindau protein (pVHL) interactions in the ubiquitinproteasome-mediated degradation of HIF-1α. However, neither inhibition of prolyl hydroxylases nor mutation of HIF-1α-hydroxylated prolines involved with pVHL-mediated binding inhibits the observed FOXO4-mediated down-regulation of HIF-1α. These results suggest a novel alternate mechanism for hypoxic regulation that is dependent upon the level of activation of FOXO4-mediated transcription. Induction of the PI3K 1The abbreviations used are: PI3K, phosphatidylinositol 3-kinase; VEGF, vascular endothelial growth factor; EPO, erythropoietin; HIF-1, hypoxia-inducible factor 1; GLUT-1, glucose transporter 1; pVHL, von Hippel-Lindau protein; DFO, deferoxamine mesylate; DOX, doxycycline hydrochloride; GFP, green fluorescent protein; AHR, aryl hydrocarbon receptor; PTEN, phosphatase with tensin homology.1The abbreviations used are: PI3K, phosphatidylinositol 3-kinase; VEGF, vascular endothelial growth factor; EPO, erythropoietin; HIF-1, hypoxia-inducible factor 1; GLUT-1, glucose transporter 1; pVHL, von Hippel-Lindau protein; DFO, deferoxamine mesylate; DOX, doxycycline hydrochloride; GFP, green fluorescent protein; AHR, aryl hydrocarbon receptor; PTEN, phosphatase with tensin homology. signaling pathway results in a diversity of survival-enhancing functions in both normal as well as oncogenically transformed cells (1Toker A. Cantley L.C. Nature. 1997; 387: 673-676Crossref PubMed Scopus (1223) Google Scholar). A large body of work in a variety of systems has revealed that activation of this pathway results in the induction of a cascade of kinases that include PDK-1 and one or more of the AKT/protein kinase B kinases (2Toker A. Newton A.C. Cell. 2000; 103: 185-188Abstract Full Text Full Text PDF PubMed Scopus (366) Google Scholar). A major end result of AKT/protein kinase B kinase activation is phosphorylation of several sites in a family of forkhead-type transcription factors that includes FOXO4 (3Ogg S. Paradis S. Gottlieb S. Patterson G.I. Lee L. Tissenbaum H.A. Ruvkun G. Nature. 1997; 389: 994-999Crossref PubMed Scopus (1536) Google Scholar, 4Brunet A. Bonni A. Zigmond M.J. Lin M.Z. Juo P. Hu L.S. Anderson M.J. Arden K.C. Blenis J. Greenberg M.E. Cell. 1999; 96: 857-868Abstract Full Text Full Text PDF PubMed Scopus (5412) Google Scholar, 5Kops G.J. de Ruiter N.D. De Vries-Smits A.M. Powell D.R. Bos J.L. 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PubMed Scopus Google Scholar, M.E. Nature. 1999; PubMed Scopus Google Scholar, M.E. N. D.R. P. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, T. S. M. Proc. Natl. Acad. Sci. U. S. A. 2000; PubMed Scopus Google Scholar, M. M. N. Biol. 2000; PubMed Scopus Google Scholar, Y. T. L. J. 2000; PubMed Google Scholar, D. J. PubMed Scopus Google Scholar, J. Cell. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar, J. M. Cell. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). have that a family of are involved with oxygen and this levels of HIF-1α prolyl hydroxylation M. H. W. J. M. A. PubMed Scopus Google Scholar, P. D.R. J. A. M. PubMed Scopus Google Scholar, N. J. 20: PubMed Scopus Google Scholar, PubMed Scopus Google Scholar, A.C. L.A. J. D.R. M. A. N. P. J. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). protein (pVHL) with and the and degradation of HIF-1α. These that levels of responses are oxygen both the PI3K and the hypoxic are regulated by the of or oxygen levels, that Previous revealed a the level of activation of the PI3K pathway and hypoxia as well as the of HIF-1α P. Mol. Cell. Biol. PubMed Scopus Google Scholar, W. D. A. F. D. 2000; PubMed Google Scholar, M. Proc. Natl. Acad. Sci. U. S. A. 2000; PubMed Scopus Google Scholar, G. T. Google Scholar, 1997; PubMed Google Scholar, N. A.L. Google Scholar, H. D. 2000; Google Scholar, Google Scholar). of the PI3K pathway by a in HIF-1α protein levels and inhibition of Here we that the transcription factor FOXO4 to hypoxia in by down-regulation of the levels of the HIF-1α of the mechanism of this down-regulation revealed by the pathway, to of a for the regulation of the by the PI3K pathway the for the involvement of forkhead transcription factor FOXO4 in the regulation of hypoxia alternate to the levels of HIF-1α and resultant HIF-1α and to expression (also known as used in the and has been T.T. Dowbenko D. Jackson A. Toney L. Lewin D.A. Dent A.L. Lasky L.A. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). and and by the and of the in the for the to and and used for the of the and the expression and to and by a and FOXO4 T.T. Dowbenko D. Jackson A. Toney L. Lewin D.A. Dent A.L. Lasky L.A. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google and in glucose with and B cells in the and M.E. Nature. 1999; PubMed Scopus Google in with and for with and used the in in and the levels to cells in and with or or and to the cells in the or of deferoxamine for and for by the as by the to the HIF-1α down-regulation or FOXO4 cells with or and in oxygen or with deferoxamine to for the of the HIF-1α protein the the cells with or doxycycline in oxygen or in the of to the or the both and cells and and to HIF-1α or and both and PI3K HIF-1α in in and have shown that activation of the PI3K/AKT signaling pathway results in expression of the HIF-1α protein and of the transcription P. Mol. Cell. Biol. PubMed Scopus Google Scholar, W. D. A. F. D. 2000; PubMed Google Scholar, M. Proc. Natl. Acad. Sci. U. S. A. 2000; PubMed Scopus Google Scholar, G. T. Google Scholar, 1997; PubMed Google Scholar, N. A.L. Google Scholar, H. D. 2000; Google Scholar). of the PI3K/AKT by the PI3K and as well as by of the phosphatase PTEN, a for activation of the PI3K/AKT pathway in the increase of the HIF-1α protein the PI3K/AKT is in cells for the induction of genes hypoxic we the cells with for in the or of a hypoxic deferoxamine and the levels of by the expression of and this increase by the of the PI3K in levels by with a in the level of HIF-1α protein expression cells with a HIF-1α expression a decreased HIF-1α protein level in the of observed in the of DFO, the HIF-1α the inhibition of the PI3K/AKT by of the HIF-1α protein the of DFO, the expression of HIF-1α and to the in the HIF-1α protein levels, the to by PI3K/AKT is in cells to induce the expression of the HIF-1α protein and for levels in to results observed cells with for Nuclear FOXO4 HIF-1α the forkhead transcription factor FOXO4 is one of the of the PI3K/AKT signaling pathway, we FOXO4 involved in the regulation of the HIF-1α protein expression. this we used by doxycycline to a of FOXO4 T.T. Dowbenko D. Jackson A. Toney L. Lewin D.A. Dent A.L. Lasky L.A. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). of the phosphorylation sites in this FOXO4 protein to to the by and in the FOXO4 a and the green fluorescent protein that this FOXO4 PI3K/AKT for increase in levels in cells with DFO, and of by the level of induction of FOXO4 in by in a down-regulation of the HIF-1α protein levels down-regulation in the of DFO, that the of the HIF-1α protein by the of DOX, FOXO4 expression and the levels of the protein as as down-regulation of the HIF-1α protein by the the FOXO4 down-regulation of the HIF-1α protein with of the protein cells revealed a of FOXO4 the expression of the HIF-1α protein with a that the protein of the HIF-1α protein cells with a expression in both the and of the of FOXO4 the down-regulation of the HIF-1α protein hypoxic and in with in Biol. 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PubMed Scopus Google Scholar). and with HIF-1α that has been and hydroxylation with HIF-1α with and FOXO4 to induce HIF-1α down-regulation in the of the that with for down-regulation of regulated by we that down-regulation of HIF-1α in the of that hydroxylation and with the of DFO, the HIF-1α by both and in by pVHL-mediated pathway and for pVHL-mediated the of the degradation and the HIF-1α protein to in of and expression of HIF-1α with the of in cells that have been by to FOXO4 to However, in the of FOXO4 the HIF-1α protein to the of in of the HIF-1α the levels FOXO4 to that hydroxylation HIF-1α essential for down-regulation of the HIF-1α we to and to and this HIF-1α protein in the observed down-regulation to pVHL, the of prolines the hydroxylation of HIF-1α protein and this of HIF-1α has been shown to and N. J. 20: PubMed Scopus Google Scholar). shown in this HIF-1α with as the protein in the of FOXO4 expression. down-regulation of HIF-1α hydroxylation the essential for with consistent with that FOXO4 down-regulation of the HIF-1α protein by a the down-regulation of the HIF-1α protein in the of the PI3K/AKT in the with to the activation of forkhead transcription in a in the HIF-1α protein levels A large body of a the PI3K/AKT signaling pathway and P. Mol. Cell. Biol. PubMed Scopus Google Scholar, W. D. A. F. D. 2000; PubMed Google Scholar, M. Proc. Natl. Acad. Sci. U. S. A. 2000; PubMed Scopus Google Scholar, G. T. Google Scholar, 1997; PubMed Google Scholar, N. A.L. Google Scholar, H. D. 2000; Google Scholar, Google Scholar). is for growth and of cells and is that of for in the of various factors that the PI3K/AKT pathway, to for the of this pathway in decreased or a for the is that the regulation of by PI3K/AKT to the to by both as well as oxygen a for the the PI3K/AKT signaling pathway and Previous have that activation of the PI3K pathway results in induction of a kinase cascade that the phosphorylation of a of forkhead transcription factors that includes FOXO4 (also known as AFX), and of factors are in the (3Ogg S. Paradis S. Gottlieb S. Patterson G.I. Lee L. Tissenbaum H.A. Ruvkun G. Nature. 1997; 389: 994-999Crossref PubMed Scopus (1536) Google Scholar, 4Brunet A. Bonni A. Zigmond M.J. Lin M.Z. Juo P. Hu L.S. Anderson M.J. Arden K.C. Blenis J. Greenberg M.E. Cell. 1999; 96: 857-868Abstract Full Text Full Text PDF PubMed Scopus (5412) Google Scholar, 5Kops G.J. de Ruiter N.D. De Vries-Smits A.M. Powell D.R. Bos J.L. Burgering B.M. Nature. 1999; 398: 630-634Crossref PubMed Scopus (950) Google Scholar, 6Tang E.D. Nunez G. Barr F.G. Guan K.L. J. Biol. Chem. 1999; 274: 16741-16746Abstract Full Text Full Text PDF PubMed Scopus (662) Google Scholar, 7Takaishi H. Konishi H. Matsuzaki H. Ono Y. Shirai Y. Saito N. Kitamura T. Ogawa W. Kasuga M. Kikkawa U. Nishizuka Y. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 11836-11841Crossref PubMed Scopus (217) Google Scholar, 8Nakamura N. Ramaswamy S. Vazquez F. Signoretti S. Loda M. Sellers W.R. Mol. Cell. Biol. 2000; 20: 8969-8982Crossref PubMed Scopus (495) Google Scholar, J. T. Arden K.C. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: PubMed Scopus Google Scholar). this family of transcription factors to the expression of and genes T.T. Dowbenko D. Jackson A. Toney L. Lewin D.A. Dent A.L. Lasky L.A. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar, S. A. S. A. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, G.J. Bos J.L. Burgering B.M. 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D. 2000; Google results that neither hypoxia nor the hypoxic deferoxamine as by phosphorylation and and the is for the HIF-1α protein expression and hypoxia that the PI3K/AKT pathway the HIF-1α protein expression in to levels of oxygen hypoxia to the of FOXO4 HIF-1α protein expression and hypoxic that the of and hypoxia the HIF-1α protein by for the observed lack of increase in phosphorylation is that the cells in PI3K/AKT in the in and that a of phosphorylation in the of and conditions. increase the level of as with functions that the PI3K/AKT pathway by to growth and to the PI3K/AKT pathway by the of PTEN, the major phosphatase involved with the down-regulation of the of suggest that the of the tumor with a to angiogenesis, that by the by the forkhead transcription a and work has that the of the results in the of the HIF-1α protein and of factors as M.E. Nature. 1999; PubMed Scopus Google Scholar, J. Cell. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar, J. M. 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PI3K/AKT the of HIF-1α the result a for and a in the down-regulation of the that FOXO4 a regulator of protein of genes that the level of protein in to FOXO4 protein has been in in cells by with and to protein F. U. 1997; PubMed Scopus Google Scholar). to expression of protein by FOXO4 is for the observed down-regulation of HIF-1α by with the of the HIF-1α we have that FOXO4 the expression of aryl hydrocarbon and with and with PubMed Scopus Google Scholar, PubMed Scopus Google Scholar, H. Mol. Cell. 1999; Scholar, S. A.L. 1999; PubMed Scopus Google Scholar). expression of to the down-regulation of HIF-1α by the binding of HIF-1α and to is to the of down-regulation of the HIF-1α suggest that down-regulation of the HIF-1α protein level is for the inhibition of of VEGF, EPO, and transcription by genes are regulated by HIF-1α. the that factors by FOXO4 are involved in the FOXO4-mediated suppression of the hypoxia and have that large of genes are by the forkhead transcription factors S. N. L. Sellers W.R. Cell. 2002; Full Text Full Text PDF PubMed Scopus Google the we genes involved in FOXO4-mediated regulation of hypoxia and the of and by with the of by the and S. A.L. 1999; PubMed Scopus Google Scholar, S. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar, G. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar). is the of a of transcription has been to essential role in tumor S. D. 20: PubMed Google Scholar, D. D. W. W. Y. Nature. 1999; PubMed Scopus Google Scholar, H.A. T. T. Cell. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). of results in a of expression and in D. D. W. W. Y. Nature. 1999; PubMed Scopus Google Scholar). H.A. T. T. Cell. 2002; Full Text Full Text PDF PubMed Scopus Google that of the Interestingly, we that expression as a result of FOXO4 consistent with FOXO4 a role in negatively Ramaswamy S. N. L. Sellers W.R. Cell. 2002; Full Text Full Text PDF PubMed Scopus Google that level by is that FOXO4 the expression of the HIF-1α protein and inhibits VEGF, EPO, and activation in to and to of the one or more genes are essential factors in FOXO4-mediated regulation of HIF-1α levels the hypoxia the HIF-1α transcription factor a diversity of including and D. A. A. 2000; PubMed Google Scholar, Lee Cell. 2002; Full Text Full Text PDF PubMed Scopus Google as well as and results that of FOXO4 is a novel and regulator of HIF-1α and the PI3K/AKT signaling pathway by the of HIF-1α protein by FOXO4 the and a of that result in the down-regulation of the HIF-1α protein levels and suppression of to are to and J. for the prolyl and W. for the and D. Lin and for the