FOXO-mediated transcription of cell cycle genes

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Homo sapiens
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FOXO transcription factors induce expression of several genes that negatively regulate proliferation of different cell types, such as erythroid progenitors (Bakker et al. 2004, Wang et al. 2015) and neuroepithelial progenitor cells in the telencephalon (Seoane et al. 2004).
Transcription of cyclin-dependent kinase (CDK) inhibitors CDKN1A (p21Cip1) is directly stimulated by FOXO1, FOXO3 and FOXO4 (Seoane et al. 2004, Tinkum et al. 2013). FOXO transcription factors can cooperate with the SMAD2/3:SMAD4 complex to induce CDKN1A transcription in response to TGF-beta signaling (Seoane et al. 2004).
FOXO transcription factors FOXO1, FOXO3 and FOXO4 stimulate transcription of the CDKN1B (p27Kip1) gene, but direct binding of FOXOs to the CDKN1B gene locus has not been demonstrated (Dijkers et al. 2000, Medema et al. 2000, Lees et al. 2008).
FOXO3 and FOXO4, and possibly FOXO1, directly stimulate transcription of the GADD45A gene (Tran et al. 2002, Furukawa Hibi et al. 2002, Hughes et al. 2011, Sengupta et al. 2011, Ju et al. 2014).
Transcription of the retinoblastoma family protein RBL2 (p130), involved in the maintenance of quiescent (G0) state, is directly stimulated by FOXO1, FOXO3 and FOXO4 (Kops et al. 2002, Chen et al. 2006).
Transcription of the anti-proliferative protein CCNG2 is directly stimulated by FOXO1 and FOXO3, and possibly FOXO4 (Martinez Gac et al. 2004, Chen et al. 2006). Transcription of the anti-proliferative protein BTG1 is directly stimulated by FOXO3 (Bakker et al. 2004, Bakker et al. 2007, Wang et al. 2015).
Transcription of CAV1, encoding caveolin-1, involved in negative regulation of growth factor receptor signaling and establishment of quiescent cell phenotype, is directly stimulated by FOXO1 and FOXO3 (van den Heuvel et al. 2005, Roy et al. 2008, Nho et al. 2013, Sisci et al. 2013).
FOXO1 and FOXO3 promote transcription of the KLF4 gene, encoding a transcription factor Krueppel-like factor 4, which inhibits proliferation of mouse B cells (Yusuf et al. 2008).
FOXO1, together with the p-2S-SMAD2/3:SMAD4 complex, stimulates transcription of the MSTN gene, encoding myostatin, a TGF-beta family member that stimulates differentiation of myoblasts (Allen and Unterman 2007).

Literature References
PubMed ID Title Journal Year
15458387 Direct control of caveolin-1 expression by FOXO transcription factors

Burgering, BM, Schulze, A, van den Heuvel, AP

Biochem. J. 2005
12048180 FOXO forkhead transcription factors induce G(2)-M checkpoint in response to oxidative stress

Ikeda, K, Motoyama, N, Ohta, T, Yoshida-Araki, K, Furukawa-Hibi, Y

J. Biol. Chem. 2002
16885393 Regulation of myostatin expression and myoblast differentiation by FoxO and SMAD transcription factors

Allen, DL, Unterman, TG

Am. J. Physiol., Cell Physiol. 2007
11884591 Control of cell cycle exit and entry by protein kinase B-regulated forkhead transcription factors

Medema, RH, Burgering, BM, Glassford, J, Kops, GJ, Lam, EW, Coffer, PJ, Essers, MA, Dijkers, PF

Mol. Cell. Biol. 2002
24452601 FOXO1-dependent DNA damage repair is regulated by JNK in lung cancer cells

Yu, A, Xu, T, Ju, Y, Zhang, H

Int. J. Oncol. 2014
25843800 Knockdown of transcription factor forkhead box O3 (FOXO3) suppresses erythroid differentiation in human cells and zebrafish

Qi, H, Liu, F, Yang, Y, Zheng, J, Zhang, Q, Wang, S, Zhang, Z, Qu, H, Li, Y, Wang, H, Fang, X

Biochem. Biophys. Res. Commun. 2015
18787071 Age-dependent FOXO regulation of p27Kip1 expression via a conserved binding motif in rat muscle precursor cells

Lees, SJ, Childs, TE, Booth, FW

Am. J. Physiol., Cell Physiol. 2008
18444242 Wild-type APC regulates caveolin-1 expression in human colon adenocarcinoma cell lines via FOXO1a and C-myc

Ignatenko, NA, Gerner, EW, Fultz, KE, Henkhaus, RS, Mora, J, Roy, UK

Mol. Carcinog. 2008
14734530 FoxO3a regulates erythroid differentiation and induces BTG1, an activator of protein arginine methyl transferase 1

Kolbus, A, Blázquez-Domingo, M, von Lindern, M, Bakker, WJ, van Dijk, TB, Steinlein, P, Besooyen, J, Coffer, PJ, Löwenberg, B, Beug, H

J. Cell Biol. 2004
17353275 Differential regulation of Foxo3a target genes in erythropoiesis

Kolbus, A, Verhaak, RG, Yamamoto, K, Mak, TW, von Lindern, M, Bakker, WJ, van Dijk, TB, Steinlein, P, Parren-van Amelsvoort, M, Löwenberg, B, Beug, H

Mol. Cell. Biol. 2007
16493026 FOXO transcription factors cooperate with delta EF1 to activate growth suppressive genes in B lymphocytes

Fruman, DA, Yusuf, I, Andersen, HM, Chen, J

J. Immunol. 2006
21159781 FoxO transcription factors promote cardiomyocyte survival upon induction of oxidative stress

DePinho, RA, Sengupta, A, Paik, JH, Molkentin, JD, Yutzey, KE

J. Biol. Chem. 2011
15084259 Integration of Smad and forkhead pathways in the control of neuroepithelial and glioblastoma cell proliferation

Massague, J, Shen, L, Le, HV, Anderson, SA, Seoane, J

Cell 2004
18375530 KLF4 is a FOXO target gene that suppresses B cell proliferation

Sareen, P, Fruman, DA, Peralta, RQ, Kaestner, KH, Kharas, MG, Yusuf, I, Maruniak, A, Yang, VW, Chen, J

Int. Immunol. 2008
11964479 DNA repair pathway stimulated by the forkhead transcription factor FOXO3a through the Gadd45 protein

Greenberg, ME, Brunet, A, Datta, SR, Tran, H, Fornace, AJ, Grenier, JM, Chiang, LW, DiStefano, PS

Science 2002
11094066 Forkhead transcription factor FKHR-L1 modulates cytokine-dependent transcriptional regulation of p27(KIP1)

Raaijmakers, JA, Burgering, BM, Banerji, L, Koenderman, L, Thomas, NS, Lammers, JW, Pals, C, Dijkers, PF, Coffer, PJ, Lam, EW, Medema, RH

Mol. Cell. Biol. 2000
23580232 FoxO3a (Forkhead Box O3a) deficiency protects Idiopathic Pulmonary Fibrosis (IPF) fibroblasts from type I polymerized collagen matrix-induced apoptosis via caveolin-1 (cav-1) and Fas

Peterson, M, Henke, CA, Nho, RS, Hergert, P

PLoS ONE 2013
21196578 FoxO1 and SIRT1 regulate beta-cell responses to nitric oxide

Corbett, JA, Hughes, KJ, Hansen, PA, Meares, GP

J. Biol. Chem. 2011
10783894 AFX-like Forkhead transcription factors mediate cell-cycle regulation by Ras and PKB through p27kip1

Burgering, BM, Bos, JL, Kops, GJ, Medema, RH

Nature 2000
23918930 Forkhead box O1 (FOXO1) protein, but not p53, contributes to robust induction of p21 expression in fasted mice

Piwnica-Worms, H, Herzog, E, White, LS, Marpegan, L, Piwnica-Worms, D, Tinkum, KL

J. Biol. Chem. 2013
14966295 Control of cyclin G2 mRNA expression by forkhead transcription factors: novel mechanism for cell cycle control by phosphoinositide 3-kinase and forkhead

Carrera, AC, Campanero, MR, García, Z, Martínez-Gac, L, Marqués, M

Mol. Cell. Biol. 2004
24047697 The estrogen receptor α is the key regulator of the bifunctional role of FoxO3a transcription factor in breast cancer motility and invasiveness

Ferraro, A, Cesario, MG, Coroniti, R, Maris, P, Romeo, F, Sisci, D, Mauro, L, Trombino, GE, Morelli, C, Aquila, S, Andó, S, Maggiolini, M, Lanzino, M, Anselmo, W

Cell Cycle 2013
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Cross References
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