The Forkhead Transcription Factor Foxo1 Bridges the JNK Pathway and the Transcription Factor PDX-1 through Its Intracellular Translocation
It has been shown that oxidative stress and activation of the c-Jun N-terminal kinase (JNK) pathway induce the nucleocytoplasmic translocation of the pancreatic transcription factor PDX-1, which leads to pancreatic β-cell dysfunction. In this study, we have shown that the forkhead transcription factor Foxo1/FKHR plays a role as a mediator between the JNK pathway and PDX-1. Under oxidative stress conditions, Foxo1 changed its intracellular localization from the cytoplasm to the nucleus in the pancreatic β-cell line HIT-T15. The overexpression of JNK also induced the nuclear localization of Foxo1, but in contrast, suppression of JNK reduced the oxidative stress-induced nuclear localization of Foxo1, suggesting the involvement of the JNK pathway in Foxo1 translocation. In addition, oxidative stress or activation of the JNK pathway decreased the activity of Akt in HIT cells, leading to the decreased phosphorylation of Foxo1 following nuclear localization. Furthermore, adenovirus-mediated Foxo1 overexpression reduced the nuclear expression of PDX-1, whereas repression of Foxo1 by Foxo1-specific small interfering RNA retained the nuclear expression of PDX-1 under oxidative stress conditions. Taken together, Foxo1 is involved in the nucleocytoplasmic translocation of PDX-1 by oxidative stress and the JNK pathway. It has been shown that oxidative stress and activation of the c-Jun N-terminal kinase (JNK) pathway induce the nucleocytoplasmic translocation of the pancreatic transcription factor PDX-1, which leads to pancreatic β-cell dysfunction. In this study, we have shown that the forkhead transcription factor Foxo1/FKHR plays a role as a mediator between the JNK pathway and PDX-1. Under oxidative stress conditions, Foxo1 changed its intracellular localization from the cytoplasm to the nucleus in the pancreatic β-cell line HIT-T15. The overexpression of JNK also induced the nuclear localization of Foxo1, but in contrast, suppression of JNK reduced the oxidative stress-induced nuclear localization of Foxo1, suggesting the involvement of the JNK pathway in Foxo1 translocation. In addition, oxidative stress or activation of the JNK pathway decreased the activity of Akt in HIT cells, leading to the decreased phosphorylation of Foxo1 following nuclear localization. Furthermore, adenovirus-mediated Foxo1 overexpression reduced the nuclear expression of PDX-1, whereas repression of Foxo1 by Foxo1-specific small interfering RNA retained the nuclear expression of PDX-1 under oxidative stress conditions. Taken together, Foxo1 is involved in the nucleocytoplasmic translocation of PDX-1 by oxidative stress and the JNK pathway. Diabetes mellitus is the most prevalent metabolic disorder all over the world. Impaired insulin secretion and whole body insulin resistance play major roles in the development and progression of diabetes. In particular, pancreatic β-cell function, such as insulin biosynthesis and secretion, is often impaired under the chronic hyperglycemic conditions found in diabetes (1Poitout V. Robertson R.P. Endocrinology. 2002; 143: 339-342Crossref PubMed Scopus (550) Google Scholar). Several lines of evidence have implicated oxidative stress in the progression of β-cell dysfunction in type 2 diabetes (1Poitout V. Robertson R.P. Endocrinology. 2002; 143: 339-342Crossref PubMed Scopus (550) Google Scholar, 2Robertson R.P. J. Biol. Chem. 2004; 279: 42351-42354Abstract Full Text Full Text PDF PubMed Scopus (828) Google Scholar, 3Matsuoka T. Kajimoto Y. Watada H. Kaneto H. Kishimoto M. Umayahara Y. Fujitani Y. Kamada T. Kawamori R. Yamasaki Y. J. Clin. Investig. 1997; 99: 144-150Crossref PubMed Scopus (290) Google Scholar, 4Tanaka Y. Gleason C.E. Tran P.O. Harmon J.S. 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Chem. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar), we the of oxidative stress the phosphorylation of Akt in HIT with insulin induced phosphorylation of Akt in a in HIT of Akt phosphorylation reduced by treatment with of insulin the phosphorylation of Akt increased to of conditions the other under oxidative stress conditions, the of Akt phosphorylation reduced to of conditions. that of protein the whole protein with an and an The the of from and are as that oxidative stress reduces the phosphorylation of which leads to an in the phosphorylation of Foxo1 and its nuclear The JNK in the of major protein kinase the JNK and kinase can be activated by a of stress signals, such as and oxidative and induce various (12Davis R.J. Cell. 2000; 103: 239-252Abstract Full Text Full Text PDF PubMed Scopus (3666) Google Scholar, 13Minden A. Karin M. Biochim. Biophys. Acta. 1997; 1333: F85-F104PubMed Google Scholar). It has been that activation of the JNK pathway is involved in β-cell dysfunction by oxidative stress (15Kaneto H. Xu G. Fujii N. Kim S. Bonner-Weir S. Weir G.C. J. Biol. Chem. 2002; 277: 30010-30018Abstract Full Text Full Text PDF PubMed Scopus (278) Google Scholar). In addition, we have recently reported that the nucleocytoplasmic translocation of PDX-1 induced by oxidative stress is by activation of the JNK pathway (16Kawamori D. Kajimoto Y. Kaneto H. Umayahara Y. Fujitani Y. Miyatsuka T. Watada H. Leibiger I.B. Yamasaki Y. Hori M. Diabetes. 2003; 52: 2896-2904Crossref PubMed Scopus (183) Google Scholar). we the of the JNK pathway in this oxidative stress-induced nuclear of a dominant negative of JNK by the of a JNK the oxidative stress-induced nuclear of Foxo1 In contrast, such effects a a JNK by of a JNK Foxo1 nuclear oxidative stress As shown in the expression of Foxo1 also changed in to the nuclear expression of in Foxo1 also induced by oxidative stress and by JNK that the oxidative stress-induced nuclear of Foxo1 is because of its translocation from the cytoplasm to the also that the JNK pathway the oxidative stress-induced nuclear translocation of with (16Kawamori D. Kajimoto Y. Kaneto H. Umayahara Y. Fujitani Y. Miyatsuka T. Watada H. Leibiger I.B. Yamasaki Y. Hori M. Diabetes. 2003; 52: 2896-2904Crossref PubMed Scopus (183) Google Scholar), nuclear expression of PDX-1 reduced by oxidative stress and overexpression of JNK and by the expression of JNK whereas the amount of whole PDX-1 PDX-1 a localization to The JNK the of the JNK pathway shown to be involved in the intracellular translocation of Foxo1 induced by oxidative we the involvement of the JNK pathway in Akt which is the of Foxo1 intracellular localization J. T. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: PubMed Scopus Google Scholar). As shown in cells to oxidative stress or JNK the phosphorylation of Akt reduced with conditions in which the other expression of a JNK by of a JNK the phosphorylation of Akt in the of oxidative stress. that of protein the whole protein with an that the oxidative stress-induced of Akt phosphorylation by the JNK pathway in pancreatic JNK is known to induce phosphorylation of insulin and thereby reduces the activity of insulin and also its Akt (17Nakatani Y. Kaneto H. Kawamori D. Hatazaki M. Miyatsuka T. Matsuoka T.A. Kajimoto Y. Matsuhisa M. Yamasaki Y. Hori M. J. Biol. Chem. 2004; 279: 45803-45809Abstract Full Text Full Text PDF PubMed Scopus (183) Google Scholar, V. Uchida T. L. R. M.F. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). as a molecular mechanism underlying this oxidative stress-induced nuclear translocation of Foxo1, the of the insulin pathway by JNK activated under oxidative stress conditions and this reduced activity of Akt also to be an upstream mechanism of the decreased phosphorylation and nuclear localization of The of protein the by the expression of nuclear and whole by Foxo1 the of the nuclear localization of Foxo1 under oxidative stress conditions. the other PDX-1 shown to its localization from the nucleus to the cytoplasm in a under oxidative stress conditions (16Kawamori D. Kajimoto Y. Kaneto H. Umayahara Y. Fujitani Y. Miyatsuka T. Watada H. Leibiger I.B. Yamasaki Y. Hori M. 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Investig. 2002; 110: PubMed Scopus Google Scholar), this translocation be an upstream mechanism of PDX-1 translocation from the nucleus to the the between Foxo1 and PDX-1 and the involvement of Foxo1 in the intracellular localization of PDX-1, we the of the overexpression or reduction of Foxo1 an wild type Foxo1 and a dominant negative of Foxo1 and a Foxo1-specific adenovirus-mediated overexpression of Foxo1 and Foxo1 and a of Foxo1-specific by nuclear protein from or cells the to the the HIT Foxo1 expression induced in the HIT cells with Foxo1 with the cells with The expression of Foxo1 by an Foxo1 because this Foxo1 is a of the J. V. D. J. 2000; PubMed Scopus Google Scholar). In nuclear protein from Foxo1 HIT cells, Foxo1 nuclear from the HIT cells The of Foxo1-specific also by nuclear protein from HIT The expression of Foxo1 reduced by of a Foxo1-specific In to the of Foxo1 expression by the nuclear expression of in the HIT cells with As shown in Foxo1 in HIT cells by of a wild type Foxo1 expression the amount of nuclear PDX-1 reduced oxidative stress or JNK The expression of Foxo1 the nuclear expression of PDX-1, with and oxidative stress. In to the in nuclear PDX-1 the whole expression of PDX-1 by the of Foxo1 As shown in the reduction in Foxo1 by a nuclear PDX-1 in the of oxidative stress. that Foxo1 the nuclear expression of PDX-1 by the intracellular localization of PDX-1 and also the involvement of Foxo1 in oxidative JNK nucleocytoplasmic translocation of PDX-1. In the study, we that oxidative stress induces the nuclear translocation of Foxo1 through activation of the JNK pathway and that Foxo1 the JNK pathway and PDX-1 through its intracellular translocation. the molecular of the of β-cell this that Foxo1 induces PDX-1 translocation under oxidative stress conditions, the mechanism underlying this is to be from this of Foxo1 to be the of Foxo1 protein The overexpression of Foxo1 by gene reduced the nuclear expression of in contrast, the reduction of Foxo1 by expression of a Foxo1-specific that reduced Foxo1 protein the nuclear expression of PDX-1 under oxidative stress conditions. the other the expression of a dominant negative of Foxo1 that can to the Foxo1 binding of its but its because of the of a the reduction of nuclear PDX-1 from oxidative stress. that the of Foxo1 in the intracellular localization of PDX-1 be to a Foxo1 is reported to PDX-1 activity by with for DNA binding to the PDX-1 T. J. Y. Y. Wright C.V. M.F. D. J. Clin. 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