FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes

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R-HSA-9615017
Type
Pathway
Species
Homo sapiens
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FOXO6, the least studied member of the FOXO family, directly stimulates transcription of PLXNA4 gene, encoding a co-factor for the semaphorin SEMA3A receptor. FOXO6-mediated regulation of PLXNA4 expression plays an important role in radial glia migration during cortical development (Paap et al. 2016).
FOXO-mediated up-regulation of genes involved in reduction of the oxidative stress burden is not specific to neurons, but plays an important role in neuronal survival and neurodegenerative diseases. FOXO3 and FOXO4, and possibly FOXO1, directly stimulate transcription of the SOD2 gene, encoding mitochondrial manganese-dependent superoxide dismutase, which converts superoxide to the less harmful hydrogen peroxide and oxygen (Kops et al. 2002, Hori et al. 2013, Araujo et al. 2011, Guan et al. 2016). FOXO4 stimulates SOD2 gene transcription in collaboration with ATXN3, a protein involved in spinocerebellar ataxia type 3 (SCA3) (Araujo et al. 2011). FOXO3 and FOXO6, and possibly FOXO1, directly stimulate transcription of the CAT gene, encoding catalase, an enzyme that converts hydrogen peroxide to water and oxygen, thus protecting cells from the oxidative stress (Awad et al. 2014, Kim et al. 2014, Rangarajan et al. 2015, Song et al. 2016, Liao et al. 2016, Guo et al. 2016).
FOXO transcription factors regulate transcription of several genes whose protein products are secreted from hypothalamic neurons to control appetite and food intake: NPY gene, AGRP gene and POMC gene. At low insulin levels, characteristic of starvation, FOXO transcription factors bind to insulin responsive elements (IRES) in the regulatory regions of NPY, AGRP and POMC gene. FOXO1 directly stimulates transcription of the NPY gene, encoding neuropeptide-Y (Kim et al. 2006, Hong et al. 2012), and the AGRP gene, encoding Agouti-related protein (Kitamura et al. 2006, Kim et al. 2006), which both stimulate food intake. At the same time, FOXO1 directly represses transcription of the POMC gene, encoding melanocyte stimulating hormone alpha , which suppresses food intake (Kitamura et al. 2006, Kim et al. 2006). When, upon food intake, blood insulin levels rise, insulin-mediated activation of PI3K/AKT signaling inhibits FOXO transcriptional activity.
In liver cells, FOXO transcription factors regulate transcription of genes involved in gluconeogenesis: G6PC gene, encoding glucose-6-phosphatase and PCK1 gene, encoding phosphoenolpyruvate carboxykinase. Actions of G6PC and PCK1 enable steady glucose blood levels during fasting. FOXO1, FOXO3 and FOXO4 directly stimulate PCK1 gene transcription (Hall et al. 2000, Yang et al. 2002, Puigserver et al. 2003), while all four FOXOs, FOXO1, FOXO3, FOXO4 and FOXO6 directly stimulate G6PC gene transcription (Yang et al. 2002, Puigserver et al. 2003, Onuma et al. 2006, Kim et al. 2011). FOXO-mediated induction of G6PC and PCK1 genes is negatively regulated by insulin-induced PI3K/AKT signaling.
FOXO1, FOXO3 and FOXO4 directly stimulate transcription of the IGFBP1 gene, encoding insulin growth factor binding protein 2 (Tang et al. 1999, Kops et al. 1999, Hall et al. 2000, Yang et al. 2002), which increases sensitivity of cells to insulin.
FOXO1 and FOXO3 directly stimulate transcription of the ABCA6 (ATP-binding cassette sub-family A member 6) gene, encoding a putative transporter protein that is thought to be involved in lipid homeostasis (Gai et al. 2013). The GCK (glucokinase) gene is another gene involved in lipid homeostasis that is regulated by FOXOs. FOXO1, acting with the SIN3A:HDAC complex, directly represses the GCK gene transcription, thus repressing lipogenesis in the absence of insulin (Langlet et al. 2017). The SREBF1 (SREBP1) gene, which encodes a transcriptional activator required for lipid homeostasis, is directly transcriptionally repressed by FOXO1 (Deng et al. 2012). Transcription of the RETN gene, encoding resistin, an adipocyte specific hormone that suppresses insulin-mediated uptake of glucose by adipose cells, is directly stimulated by FOXO1 (Liu et al. 2014).
Transcription of two genes encoding E3 ubiquitin ligases FBXO32 (Atrogin-1) and TRIM63 (MURF1), involved in degradation of muscle proteins and muscle wasting during starvation, is positively regulated by FOXO transcription factors (Sandri et al. 2004, Waddell et al. 2008, Raffaello et al. 2010, Senf et al. 2011, Bollinger et al. 2014, Wang et al. 2017).

Literature References
PubMed ID Title Journal Year
27869526 PGC-1α over-expression suppresses the skeletal muscle atrophy and myofiber-type composition during hindlimb unloading

Wang, J, Wang, F, Zhang, P, Liu, H, He, J, Zhang, C, Fan, M, Chen, X

Biosci. Biotechnol. Biochem. 2017
26700816 TNF-α Inhibits FoxO1 by Upregulating miR-705 to Aggravate Oxidative Damage in Bone Marrow-Derived Mesenchymal Stem Cells during Osteoporosis

Liao, L, Su, X, Yang, X, Hu, C, Li, B, Lv, Y, Shuai, Y, Jing, H, Deng, Z, Jin, Y

Stem Cells 2016
22511764 FoxO1 inhibits sterol regulatory element-binding protein-1c (SREBP-1c) gene expression via transcription factors Sp1 and SREBP-1c

Deng, X, Zhang, W, O-Sullivan, I, Williams, JB, Dong, Q, Park, EA, Raghow, R, Unterman, TG, Elam, MB

J. Biol. Chem. 2012
27547294 CD38 Deficiency Protects the Heart from Ischemia/Reperfusion Injury through Activating SIRT1/FOXOs-Mediated Antioxidative Stress Pathway

Guan, XH, Liu, XH, Hong, X, Zhao, N, Xiao, YF, Wang, LF, Tang, L, Jiang, K, Qian, YS, Deng, KY, Ji, G, Fu, M, Xin, HB

Oxid Med Cell Longev 2016
22876196 Minibrain/Dyrk1a regulates food intake through the Sir2-FOXO-sNPF/NPY pathway in Drosophila and mammals

Hong, SH, Lee, KS, Kwak, SJ, Kim, AK, Bai, H, Jung, MS, Kwon, OY, Song, WJ, Tatar, M, Yu, K

PLoS Genet. 2012
16840535 Correlation between FOXO1a (FKHR) and FOXO3a (FKHRL1) binding and the inhibition of basal glucose-6-phosphatase catalytic subunit gene transcription by insulin

Onuma, H, Vander Kooi, BT, Boustead, JN, Oeser, JK, O'Brien, RM

Mol. Endocrinol. 2006
11779849 An mRNA splice variant of the AFX gene with altered transcriptional activity

Yang, Z, Whelan, J, Babb, R, Bowen, BR

J. Biol. Chem. 2002
29056338 Selective Inhibition of FOXO1 Activator/Repressor Balance Modulates Hepatic Glucose Handling

Langlet, F, Haeusler, RA, Lindén, D, Ericson, E, Norris, T, Johansson, A, Cook, JR, Aizawa, K, Wang, L, Buettner, C, Accili, D

Cell 2017
26523980 Sirtuin 3 regulates Foxo3a-mediated antioxidant pathway in microglia

Rangarajan, P, Karthikeyan, A, Lu, J, Ling, EA, Dheen, ST

Neuroscience 2015
24291305 The forkhead transcription factor FOXO1 stimulates the expression of the adipocyte resistin gene

Liu, CW, Yang, SY, Lin, CK, Liu, HS, Ho, LT, Wu, LY, Lee, MJ, Ku, HC, Chang, HH, Huang, RN, Kao, YH

Gen. Comp. Endocrinol. 2014
25007762 The essential role of FoxO6 phosphorylation in aging and calorie restriction

Kim, DH, Park, MH, Chung, KW, Kim, MJ, Jung, YR, Bae, HR, Jang, EJ, Lee, JS, Im, DS, Yu, BP, Chung, HY

Age (Dordr) 2014
10913147 Regulation of phosphoenolpyruvate carboxykinase and insulin-like growth factor-binding protein-1 gene expression by insulin. The role of winged helix/forkhead proteins

Hall, RK, Yamasaki, T, Kucera, T, Waltner-Law, M, O'Brien, R, Granner, DK

J. Biol. Chem. 2000
21389279 p300 Acetyltransferase activity differentially regulates the localization and activity of the FOXO homologues in skeletal muscle

Senf, SM, Sandesara, PB, Reed, SA, Judge, AR

Am. J. Physiol., Cell Physiol. 2011
26052839 Lentiviral Vector-Mediated FoxO1 Overexpression Inhibits Extracellular Matrix Protein Secretion Under High Glucose Conditions in Mesangial Cells

Guo, F, Wang, Q, Zhou, Y, Wu, L, Ma, X, Liu, F, Huang, F, Qin, G

J. Cell. Biochem. 2016
12239572 Forkhead transcription factor FOXO3a protects quiescent cells from oxidative stress

Kops, GJ, Dansen, TB, Polderman, PE, Saarloos, I, Wirtz, KW, Coffer, PJ, Huang, TT, Bos, JL, Medema, RH, Burgering, BM

Nature 2002
24167160 AMPK and FoxO1 regulate catalase expression in hypoxic pulmonary arterial smooth muscle

Awad, H, Nolette, N, Hinton, M, Dakshinamurti, S

Pediatr. Pulmonol. 2014
16604086 Forkhead protein FoxO1 mediates Agrp-dependent effects of leptin on food intake

Kitamura, T, Feng, Y, Kitamura, YI, Chua, SC, Xu, AW, Barsh, GS, Rossetti, L, Accili, D

Nat. Med. 2006
24920680 SMAD3 augments FoxO3-induced MuRF-1 promoter activity in a DNA-binding-dependent manner

Bollinger, LM, Witczak, CA, Houmard, JA, Brault, JJ

Am. J. Physiol., Cell Physiol. 2014
10358014 Negative regulation of the forkhead transcription factor FKHR by Akt

Tang, ED, Núñez, G, Barr, FG, Guan, KL

J. Biol. Chem. 1999
20921137 JunB transcription factor maintains skeletal muscle mass and promotes hypertrophy

Raffaello, A, Milan, G, Masiero, E, Carnio, S, Lee, D, Lanfranchi, G, Goldberg, AL, Sandri, M

J. Cell Biol. 2010
18612045 The glucocorticoid receptor and FOXO1 synergistically activate the skeletal muscle atrophy-associated MuRF1 gene

Waddell, DS, Baehr, LM, van den Brandt, J, Johnsen, SA, Reichardt, HM, Furlow, JD, Bodine, SC

Am. J. Physiol. Endocrinol. Metab. 2008
24040102 Regulation of FOXOs and p53 by SIRT1 modulators under oxidative stress

Hori, YS, Kuno, A, Hosoda, R, Horio, Y

PLoS ONE 2013
15109499 Foxo transcription factors induce the atrophy-related ubiquitin ligase atrogin-1 and cause skeletal muscle atrophy

Sandri, M, Sandri, C, Gilbert, A, Skurk, C, Calabria, E, Picard, A, Walsh, K, Schiaffino, S, Lecker, SH, Goldberg, AL

Cell 2004
10217147 Direct control of the Forkhead transcription factor AFX by protein kinase B

Kops, GJ, de Ruiter, ND, De Vries-Smits, AM, Powell, DR, Bos, JL, Burgering, BM

Nature 1999
27731402 Melatonin improves age-induced fertility decline and attenuates ovarian mitochondrial oxidative stress in mice

Song, C, Peng, W, Yin, S, Zhao, J, Fu, B, Zhang, J, Mao, T, Wu, H, Zhang, Y

Sci Rep 2016
24028821 FoxO regulates expression of ABCA6, an intracellular ATP-binding-cassette transporter responsive to cholesterol

Gai, J, Ji, M, Shi, C, Li, W, Chen, S, Wang, Y, Li, H

Int. J. Biochem. Cell Biol. 2013
21536589 FOXO4-dependent upregulation of superoxide dismutase-2 in response to oxidative stress is impaired in spinocerebellar ataxia type 3

Araujo, J, Breuer, P, Dieringer, S, Krauss, S, Dorn, S, Zimmermann, K, Pfeifer, A, Klockgether, T, Wuellner, U, Evert, BO

Hum. Mol. Genet. 2011
16783365 Role of hypothalamic Foxo1 in the regulation of food intake and energy homeostasis

Kim, MS, Pak, YK, Jang, PG, Namkoong, C, Choi, YS, Won, JC, Kim, KS, Kim, SW, Kim, HS, Park, JY, Kim, YB, Lee, KU

Nat. Neurosci. 2006
21940782 FoxO6 integrates insulin signaling with gluconeogenesis in the liver

Kim, DH, Perdomo, G, Zhang, T, Slusher, S, Lee, S, Phillips, BE, Fan, Y, Giannoukakis, N, Gramignoli, R, Strom, S, Ringquist, S, Dong, HH

Diabetes 2011
12754525 Insulin-regulated hepatic gluconeogenesis through FOXO1-PGC-1alpha interaction

Puigserver, P, Rhee, J, Donovan, J, Walkey, CJ, Yoon, JC, Oriente, F, Kitamura, Y, Altomonte, J, Dong, H, Accili, D, Spiegelman, BM

Nature 2003
27791111 FoxO6 affects Plxna4-mediated neuronal migration during mouse cortical development

Paap, RH, Oosterbroek, S, Wagemans, CM, von Oerthel, L, Schellevis, RD, Vastenhouw-van der Linden, AJ, Groot Koerkamp, MJ, Hoekman, MF, Smidt, MP

Proc. Natl. Acad. Sci. U.S.A. 2016
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