Phosphorylation and acetylation modifications of FOXO3a: Independently or synergistically? (Review)

Wang,Xianwang; Hu,Shujuan; Liu,Lei

doi:10.3892/ol.2017.5851

Phosphorylation and acetylation modifications of FOXO3a: Independently or synergistically? (Review)

Authors:
- Xianwang Wang
- Shujuan Hu
- Lei Liu
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Affiliations: Laboratory of The Neuronal Network and Brain Diseases Modulation, School of Medicine, Yangtze University, Jingzhou, Hubei 434023, P.R. China, Institute of Physical Education, Yangtze University, Jingzhou, Hubei 434023, P.R. China, MOE Key Laboratory of Laser Life Science and Institute of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, Guangdong 510631, P.R. China
Published online on: March 13, 2017 https://doi.org/10.3892/ol.2017.5851
Pages: 2867-2872
Copyright: © Wang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Forkhead box class O 3a (FOXO3a) is a transcription factor that has emerged as being a tumor suppressor and longevity factor. The precise regulation of FOXO3a transactivation of target genes is achieved via post-translational modifications (PTMs) and specific protein‑protein interactions. The multiple types of PTMs that FOXO3a undergoes, including phosphorylation, acetylation, methylation and ubiquitination, serve important roles in directing its subcellular localization and transcription activity, which are central to the integration of insulin/growth factor signaling and oxidative/nutrient stress signaling. The present review summarizes the modifications of FOXO3a that occur via phosphorylation and acetylation. In addition, the synergistic effect of multiple phosphorylations on FOXO3a and the crosstalk between phosphorylation and acetylation in the regulation of FOXO3a are discussed. These discussions may highlight potential strategies for the prevention of cancer and aging.

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1	Calnan DR and Brunet A: The FoxO code. Oncogene. 27:2276–2288. 2008. View Article : Google Scholar : PubMed/NCBI
2	Wang J, Liu S, Yin Y, Li M, Wang B, Yang L and Jiang Y: FOXO3-mediated up-regulation of Bim contributes to rhein-induced cancer cell apoptosis. Apoptosis. 20:399–409. 2015. View Article : Google Scholar : PubMed/NCBI
3	Kloet DE and Burgering BM: The PKB/FOXO switch in aging and cancer. Biochim Biophys Acta. 1813:1926–1937. 2011. View Article : Google Scholar : PubMed/NCBI
4	Wang XW, Chen WR and Xing D: A pathway from JNK through decreased ERK and Akt activities for FOXO3a nuclear translocation in response to UV irradiation. J Cell Physiol. 227:1168–1178. 2012. View Article : Google Scholar : PubMed/NCBI
5	Zhou J, Liao W, Yang J, Ma K, Li X, Wang Y, Wang D, Wang L, Zhang Y, Yin Y, et al: FOXO3 induces FOXO1-dependent autophagy by activating the AKT1 signaling pathway. Autophagy. 8:1712–1723. 2012. View Article : Google Scholar : PubMed/NCBI
6	Wang M, Zhang X, Zhao H, Wang Q and Pan Y: FoxO gene family evolution in vertebrates. BMC Evol Biol. 9:2222009. View Article : Google Scholar : PubMed/NCBI
7	Clark KL, Halay ED, Lai E and Burley SK: Co-crystal structure of the HNF-3/fork head DNA-recognition motif resembles histone H5. Nature. 364:412–420. 1993. View Article : Google Scholar : PubMed/NCBI
8	Obsil T and Obsilova V: Structural basis for DNA recognition by FOXO proteins. Biochim Biophys Acta. 1813:1946–1953. 2011. View Article : Google Scholar : PubMed/NCBI
9	Wang F, Marshall CB, Yamamoto K, Li GY, Plevin MJ, You H, Mak TW and Ikura M: Biochemical and structural characterization of an intramolecular interaction in FOXO3a and its binding with p53. J Mol Biol. 384:590–603. 2008. View Article : Google Scholar : PubMed/NCBI
10	Wang F, Marshall CB, Yamamoto K, Li GY, Gasmi-Seabrook GM, Okada H, Mak TW and Ikura M: Structures of KIX domain of CBP in complex with two FOXO3a transactivation domains reveal promiscuity and plasticity in coactivator recruitment. Proc Natl Acad Sci USA. 109:6078–6083. 2012. View Article : Google Scholar : PubMed/NCBI
11	Boccitto M and Kalb RG: Regulation of foxo-dependent transcription by post-translational modifications. Curr Drug Targets. 12:1303–1310. 2011. View Article : Google Scholar : PubMed/NCBI
12	Zhao Y, Wang Y and Zhu WG: Applications of post-translational modifications of FoxO family proteins in biological functions. J Mol Cell Biol. 3:276–282. 2011. View Article : Google Scholar : PubMed/NCBI
13	Hu MC, Lee DF, Xia W, Golfman LS, Ou-Yang F, Yang JY, Zou Y, Bao S, Hanada N, Saso H, et al: IkappaB kinase promotes tumorigenesis through inhibition of forkhead FOXO3a. Cell. 117:225–237. 2004. View Article : Google Scholar : PubMed/NCBI
14	Essers MA, Weijzen S, de Vries-Smits AM, Saarloos I, de Ruiter ND, Bos JL and Burgering BM: FOXO transcription factor activation by oxidative stress mediated by the small GTPaseRal and JNK. EMBO J. 23:4802–4812. 2004. View Article : Google Scholar : PubMed/NCBI
15	Lehtinen MK, Yuan Z, Boag PR, Yang Y, Villén J, Becker EB, DiBacco S, de la Iglesia N, Gygi S, Blackwell TK and Bonni A: A conserved MST-FOXO signaling pathway mediates oxidative-stress responses and extends life span. Cell. 125:987–1001. 2006. View Article : Google Scholar : PubMed/NCBI
16	Brunet A, Sweeney LB, Sturgill JF, Chua KF, Greer PL, Lin Y, Tran H, Ross SE, Mostoslavsky R, Cohen HY, et al: Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. Science. 303:2011–2015. 2004. View Article : Google Scholar : PubMed/NCBI
17	Daitoku H, Sakamaki J and Fukamizu A: Regulation of FoxO transcription factors by acetylation and protein-protein interactions. Biochim Biophys Acta. 1813:1954–1960. 2011. View Article : Google Scholar : PubMed/NCBI
18	Nakagawa T and Guarente L: Sirtuins at a glance. J Cell Sci. 124:833–838. 2011. View Article : Google Scholar : PubMed/NCBI
19	Wang F, Nguyen M, Qin FX and Tong Q: SIRT2 deacetylates FOXO3a in response to oxidative stress and caloric restriction. Aging Cell. 6:505–514. 2007. View Article : Google Scholar : PubMed/NCBI
20	Brunet A, Bonni A, Zigmond MJ, Lin MZ, Juo P, Hu LS, Anderson MJ, Arden KC, Blenis J and Greenberg ME: Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell. 96:857–868. 1999. View Article : Google Scholar : PubMed/NCBI
21	Dobson M, Ramakrishnan G, Ma S, Kaplun L, Balan V, Fridman R and Tzivion G: Bimodal regulation of FoxO3 by AKT and 14-3-3. Biochim Biophys Acta. 1813:1453–1464. 2011. View Article : Google Scholar : PubMed/NCBI
22	Brunet A, Park J, Tran H, Hu LS, Hemmings BA and Greenberg ME: Protein kinase SGK mediates survival signals by phosphorylating the forkhead transcription factor FKHRL1 (FOXO3a). Mol Cell Biol. 21:952–965. 2001. View Article : Google Scholar : PubMed/NCBI
23	Yang JY, Zong CS, Xia W, Yamaguchi H, Ding Q, Xie X, Lang JY, Lai CC, Chang CJ, Huang WC, et al: ERK promotes tumorigenesis by inhibiting FOXO3a via MDM2-mediated degradation. Nat Cell Biol. 10:138–148. 2008. View Article : Google Scholar : PubMed/NCBI
24	Rena G, Woods YL, Prescott AR, Peggie M, Unterman TG, Williams MR and Cohen P: Two novel phosphorylation sites on FKHR that are critical for its nuclear exclusion. EMBO J. 21:2263–2271. 2002. View Article : Google Scholar : PubMed/NCBI
25	Woods YL, Rena G, Morrice N, Barthel A, Becker W, Guo S, Unterman TG and Cohen P: The kinase DYRK1A phosphorylates the transcription factor FKHR at Ser329 in vitro, a novel in vivo phosphorylation site. Biochem J. 355:597–607. 2001. View Article : Google Scholar : PubMed/NCBI
26	Gao J, Yang X, Yin P, Hu W, Liao H, Miao Z, Pan C and Li N: The involvement of FoxO in cell survival and chemosensitivity mediated by Mirk/Dyrk1B in ovarian cancer. Int J Oncol. 40:1203–1209. 2012.PubMed/NCBI
27	Tikhanovich I, Kuravi S, Campbell RV, Kharbanda KK, Artigues A, Villar MT and Weinman SA: Regulation of FOXO3 by phosphorylation and methylation in hepatitis C virus infection and alcohol exposure. Hepatology. 59:58–70. 2014. View Article : Google Scholar : PubMed/NCBI
28	Greer EL, Oskoui PR, Banko MR, Maniar JM, Gygi MP, Gygi SP and Brunet A: The energy sensor AMP-activated protein kinase directly regulates the mammalian FOXO3 transcription factor. J BiolChem. 282:30107–30119. 2007.
29	Ho KK, McGuire VA, Koo CY, Muir KW, de Olano N, Maifoshie E, Kelly DJ, McGovern UB, Monteiro LJ, Gomes AR, et al: Phosphorylation of FOXO3a on Ser-7 by p38 promotes its nuclear localization in response to doxorubicin. J Biol Chem. 287:1545–1555. 2012. View Article : Google Scholar : PubMed/NCBI
30	Giamas G, Filipović A, Jacob J, Messier W, Zhang H, Yang D, Zhang W, Shifa BA, Photiou A, Tralau-Stewart C, et al: Kinome screening for regulators of the estrogen receptor identifies LMTK3 as a new therapeutic target in breast cancer. Nat Med. 17:715–719. 2011. View Article : Google Scholar : PubMed/NCBI
31	Liu P, Kao TP and Huang H: CDK1 promotes cell proliferation and survival via phosphorylation and inhibition of FOXO1 transcription factor. Oncogene. 27:4733–4744. 2008. View Article : Google Scholar : PubMed/NCBI
32	Huang H, Regan KM, Lou Z, Chen J and Tindall DJ: CDK2-dependent phosphorylation of FOXO1 as an apoptotic response to DNA damage. Science. 314:294–297. 2006. View Article : Google Scholar : PubMed/NCBI
33	Yuan Z, Becker EB, Merlo P, Yamada T, DiBacco S, Konishi Y, Schaefer EM and Bonni A: Activation of FOXO1 by Cdk1 in cycling cells and postmitotic neurons. Science. 319:1665–1668. 2008. View Article : Google Scholar : PubMed/NCBI
34	Bi W, Xiao L, Jia Y, Wu J, Xie Q, Ren J, Ji G and Yuan Z: c-Jun N-terminal kinase enhances MST1-mediated pro-apoptotic signaling through phosphorylation at serine 82. J Biol Chem. 285:6259–6264. 2010. View Article : Google Scholar : PubMed/NCBI
35	Yuan Z, Kim D, Shu S, Wu J, Guo J, Xiao L, Kaneko S, Coppola D and Cheng JQ: Phosphoinositide 3-kinase/Akt inhibits MST1-mediated pro-apoptotic signaling through phosphorylation of threonine 120. J Biol Chem. 285:3815–3824. 2010. View Article : Google Scholar : PubMed/NCBI
36	Chao Y, Wang Y, Liu X, Ma P, Shi Y, Gao J, Shi Q, Hu J, Yu R and Zhou X: Mst1 regulates glioma cell proliferation via the AKT/mTOR signaling pathway. J Neurooncol. 121:279–288. 2015. View Article : Google Scholar : PubMed/NCBI
37	van der Heide LP and Smidt MP: Regulation of FoxO activity by CBP/p300-mediated acetylation. Trends Biochem Sci. 30:81–86. 2005. View Article : Google Scholar : PubMed/NCBI
38	Daitoku H, Hatta M, Matsuzaki H, Aratani S, Ohshima T, Miyagishi M, Nakajima T and Fukamizu A: Silent information regulator 2 potentiates Foxo1-mediated transcription through its deacetylase activity. Proc Natl Acad Sci USA. 101:10042–10047. 2004. View Article : Google Scholar : PubMed/NCBI
39	van der Horst A, Tertoolen LG, de Vries-Smits LM, Frye RA, Medema RH and Burgering BM: FOXO4 is acetylated upon peroxide stress and deacetylated by the longevity protein hSir2(SIRT1). J Biol Chem. 279:28873–28879. 2004. View Article : Google Scholar : PubMed/NCBI
40	Bertaggia E, Coletto L and Sandri M: Posttranslational modifications control FoxO3 activity during denervation. Am J Physiol Cell Physiol. 302:C587–C596. 2012. View Article : Google Scholar : PubMed/NCBI
41	Senf SM, Sandesara PB, Reed SA and Judge AR: p300 Acetyltransferase activity differentially regulates the localization and activity of the FOXO homologues in skeletal muscle. Am J Physiol Cell Physiol. 300:C1490–C1501. 2011. View Article : Google Scholar : PubMed/NCBI
42	Matsuzaki H, Daitoku H, Hatta M, Aoyama H, Yoshimochi K and Fukamizu A: Acetylation of Foxo1 alters its DNA-binding ability and sensitivity to phosphorylation. Proc Natl Acad Sci USA. 102:11278–11283. 2005. View Article : Google Scholar : PubMed/NCBI
43	Ferguson D, Shao N, Heller E, Feng J, Neve R, Kim HD, Call T, Magazu S, Shen L and Nestler EJ: SIRT1-FOXO3a regulate cocaine actions in the nucleus accumbens. J Neurosci. 35:3100–3111. 2015. View Article : Google Scholar : PubMed/NCBI
44	Motta MC, Divecha N, Lemieux M, Kamel C, Chen D, Gu W, Bultsma Y, McBurney M and Guarente L: Mammalian SIRT1 represses forkhead transcription factors. Cell. 116:551–563. 2004. View Article : Google Scholar : PubMed/NCBI
45	Wang YQ, Cao Q, Wang F, Huang LY, Sang TT, Liu F and Chen SY: SIRT1 protects against oxidative stress-induced endothelial progenitor cells apoptosis by inhibiting FOXO3a via FOXO3a ubiquitination and degradation. J Cell Physiol. 230:2098–2107. 2015. View Article : Google Scholar : PubMed/NCBI
46	Wang F, Marshall CB, Li GY, Yamamoto K, Mak TW and Ikura M: Synergistic interplay between promoter recognition and CBP/p300 coactivator recruitment by FOXO3a. ACS Chem Biol. 4:1017–1027. 2009. View Article : Google Scholar : PubMed/NCBI
47	Cantó C, Gerhart-Hines Z, Feige JN, Lagouge M, Noriega L, Milne JC, Elliott PJ, Puigserver P and Auwerx J: AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity. Nature. 458:1056–1060. 2009. View Article : Google Scholar : PubMed/NCBI