Skip to main content
SpringerLink
Log in

Introduction to FOXO Biology

  • Protocol
  • First Online:
FOXO Transcription Factors

Part of the book series: Methods in Molecular Biology ((MIMB,volume 1890))

Abstract

Forkhead box O (FOXO) proteins are a family of transcription factors with four members in mammals, namely FOXO1, FOXO3a, FOXO4, and FOXO6. FOXO factors, originally identified as downstream regulators of the insulin pathway, are known to bind to the promoters of a broad variety of target genes and control several processes of key importance for cellular homeostasis including cellular energy production, oxidative stress resistance, and cell viability and proliferation. Accordingly, deregulation of FOXO proteins has been shown to play an essential role in metabolic disorders, human longevity, and the suppression of tumors. As the activity of these transcription factors is controlled by posttranslational modifications, inactivation of FOXOs occurs mostly due to the overactivation of their upstream modifying enzymes providing a wealth of possibilities for restoring FOXO activity pharmaceutically.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Protocol
USD 49.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 89.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 119.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Dansen TB, Burgering BMT (2008) Unravelling the tumor-suppressive functions of FOXO proteins. Trends Cell Biol 18:421–429

    Article  CAS  Google Scholar 

  2. Brunet A, Bonni A, Zigmond MJ, Lin MZ, Juo P, Hu LS, Anderson MJ, Arden KC, Blenis J, Greenberg ME (1999) Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 96:857–868

    Article  CAS  Google Scholar 

  3. Obsil T, Obsilova V (2011) Structural basis for DNA recognition by FOXO proteins. Biochim Biophys Acta 1813:1946–1953

    Article  CAS  Google Scholar 

  4. Hosaka T, Biggs WH 3rd, Tieu D, Boyer AD, Varki NM, Cavenee WK, Arden KC (2004) Disruption of forkhead transcription factor (FOXO) family members in mice reveals their functional diversification. Proc Natl Acad Sci U S A 101:2975–2980

    Article  CAS  Google Scholar 

  5. Paik JH, Kollipara R, Chu G, Ji H, Xiao Y, Ding Z, Miao L, Tothova Z, Horner JW, Carrasco DR, Jiang S, Gilliland DG, Chin L, Wong WH, Castrillon DH, DePinho R a (2007) FoxOs are lineage-restricted redundant tumor suppressors and regulate endothelial cell homeostasis. Cell 128:309–323

    Article  CAS  Google Scholar 

  6. Tothova Z, Kollipara R, Huntly BJ, Lee BH, Castrillon DH, Cullen DE, McDowell EP, Lazo-Kallanian S, Williams IR, Sears C, Armstrong SA, Passegue E, DePinho RA, Gilliland DG (2007) FoxOs are critical mediators of hematopoietic stem cell resistance to physiologic oxidative stress. Cell 128:325–339

    Article  CAS  Google Scholar 

  7. Hannenhalli S, Kaestner KH (2009) The evolution of Fox genes and their role in development and disease. Nat Rev Genet 10:233–240

    Article  CAS  Google Scholar 

  8. Santo EE, Paik J (2018) A splice junction-targeted CRISPR approach (spJCRISPR) reveals human FOXO3B to be a protein-coding gene. Gene 673:95–101

    Article  CAS  Google Scholar 

  9. Potente M, Urbich C, Sasaki K, Hofmann WK, Heeschen C, Aicher A, Kollipara R, DePinho RA, Zeiher AM, Dimmeler S (2005) Involvement of Foxo transcription factors in angiogenesis and postnatal neovascularization. J Clin Invest 115:2382–2392

    Article  CAS  Google Scholar 

  10. Salih DA, Brunet A (2008) FoxO transcription factors in the maintenance of cellular homeostasis during aging. Curr Opin Cell Biol 20:126–136

    Article  CAS  Google Scholar 

  11. Jacobs FMJ, van der Heide LP, Wijchers PJEC, Burbach JPH, Hoekman MFM, Smidt MP (2003) FoxO6, a novel member of the FoxO class of transcription factors with distinct shuttling dynamics. J Biol Chem 278:35959–35967

    Article  CAS  Google Scholar 

  12. Myatt SS, Lam EW (2007) The emerging roles of forkhead box (Fox) proteins in cancer. Nat Rev Cancer 7:847–859

    Article  CAS  Google Scholar 

  13. Calnan DR, Brunet A (2008) The FoxO code. Oncogene 27:2276–2288

    Article  CAS  Google Scholar 

  14. Ramaswamy S, Nakamura N, Sansal I, Bergeron L, Sellers WR (2002) A novel mechanism of gene regulation and tumor suppression by the transcription factor FKHR. Cancer Cell 2:81–91

    Article  CAS  Google Scholar 

  15. Eijkelenboom A, Burgering BM (2013) FOXOs: signalling integrators for homeostasis maintenance. Nat Rev Mol Cell Biol 14:83–97

    Article  CAS  Google Scholar 

  16. van der Vos KE, Coffer PJ (2011) The extending network of FOXO transcriptional target genes. Antioxid Redox Signal 14:579–592

    Article  Google Scholar 

  17. Link W, Fernandez-Marcos PJ (2017) FOXO transcription factors at the interface of metabolism and cancer. Int J Cancer 141:2379–2391

    Article  CAS  Google Scholar 

  18. Coomans de Brachene A, Demoulin JB (2016) FOXO transcription factors in cancer development and therapy. Cell Mol Life Sci 73:1159–1172

    Article  CAS  Google Scholar 

  19. Martins R, Lithgow GJ, Link W (2016) Long live FOXO: unraveling the role of FOXO proteins in aging and longevity. Aging Cell 15:196–207

    Article  CAS  Google Scholar 

  20. Kenyon CJ (2010) The genetics of ageing. Nature 464:504–512

    Article  CAS  Google Scholar 

  21. Morris BJ, Willcox DC, Donlon TA, Willcox BJ (2015) FOXO3: a major gene for human longevity - a mini-review. Gerontology 61(6):515–525

    Article  CAS  Google Scholar 

  22. Li Y, Wang W-JJ, Cao H, Lu J, Wu C, Hu F-YY, Guo J, Zhao L, Yang F, Zhang Y-XX, Li W, Zheng G-YY, Cui H, Chen X, Zhu Z, He H, Dong B, Mo X, Zeng Y, Tian X-LL (2009) Genetic association of FOXO1A and FOXO3A with longevity trait in Han Chinese populations. Hum Mol Genet 18:4897–4904

    Article  CAS  Google Scholar 

  23. Grossi V, Forte G, Sanese P, Peserico A, Tezil T, Lepore Signorile M, Fasano C, Lovaglio R, Bagnulo R, Loconte DC, Susca FC, Resta N, Simone C (2018) The longevity SNP rs2802292 uncovered: HSF1 activates stress-dependent expression of FOXO3 through an intronic enhancer. Nucleic Acids Res 46:5587–5600

    Article  CAS  Google Scholar 

  24. Donlon TA, Morris BJ, Chen R, Masaki KH, Allsopp RC, Willcox DC, Elliott A, Willcox BJ (2017) FOXO3 longevity interactome on chromosome 6. Aging Cell 16:1016–1025

    Article  CAS  Google Scholar 

  25. Tenbaum SP, Ordonez-Moran P, Puig I, Chicote I, Arques O, Landolfi S, Fernandez Y, Herance JR, Gispert JD, Mendizabal L, Aguilar S, Ramon y Cajal S, Schwartz S Jr, Vivancos A, Espin E, Rojas S, Baselga J, Tabernero J, Munoz A, Palmer HG (2012) beta-catenin confers resistance to PI3K and AKT inhibitors and subverts FOXO3a to promote metastasis in colon cancer. Nat Med 18:892–901

    Article  CAS  Google Scholar 

  26. Sandri M, Lin J, Handschin C, Yang W, Arany ZP, Lecker SH, Goldberg AL, Spiegelman BM (2006) PGC-1alpha protects skeletal muscle from atrophy by suppressing FoxO3 action and atrophy-specific gene transcription. Proc Natl Acad Sci U S A 103:16260–16265

    Article  CAS  Google Scholar 

  27. Baar MP, Brandt RMC, Putavet DA, Klein JDD, Derks KWJ, Bourgeois BRM, Stryeck S, Rijksen Y, van Willigenburg H, Feijtel DA, van der Pluijm I, Essers J, van Cappellen WA, van WF IJ, Houtsmuller AB, Pothof J, de Bruin RWF, Madl T, Hoeijmakers JHJ, Campisi J, de Keizer PLJ (2017) Targeted apoptosis of senescent cells restores tissue homeostasis in response to chemotoxicity and aging. Cell 169(132–147):e116

    Google Scholar 

  28. Bartholome A, Kampkotter A, Tanner S, Sies H, Klotz LO (2010) Epigallocatechin gallate-induced modulation of FoxO signaling in mammalian cells and C. elegans: FoxO stimulation is masked via PI3K/Akt activation by hydrogen peroxide formed in cell culture. Arch Biochem Biophys 501:58–64

    Article  CAS  Google Scholar 

  29. Wan QL, Zheng SQ, Wu GS, Luo HR (2013) Aspirin extends the lifespan of Caenorhabditis elegans via AMPK and DAF-16/FOXO in dietary restriction pathway. Exp Gerontol 48:499–506

    Article  CAS  Google Scholar 

  30. Tseng PC, Hou SM, Chen RJ, Peng HW, Hsieh CF, Kuo ML, Yen ML (2011) Resveratrol promotes osteogenesis of human mesenchymal stem cells by upregulating RUNX2 gene expression via the SIRT1/FOXO3A axis. J Bone Miner Res 26:2552–2563

    Article  CAS  Google Scholar 

  31. Golegaonkar S, Tabrez SS, Pandit A, Sethurathinam S, Jagadeeshaprasad MG, Bansode S, Sampathkumar SG, Kulkarni MJ, Mukhopadhyay A (2015) Rifampicin reduces advanced glycation end products and activates DAF-16 to increase lifespan in Caenorhabditis elegans. Aging Cell 14:463–473

    Article  CAS  Google Scholar 

  32. Link W, Oyarzabal J, Serelde BG, Albarran MI, Rabal O, Cebria A, Alfonso P, Fominaya J, Renner O, Peregrina S, Soilan D, Ceballos PA, Hernandez AI, Lorenzo M, Pevarello P, Granda TG, Kurz G, Carnero A, Bischoff JR (2009) Chemical interrogation of FOXO3a nuclear translocation identifies potent and selective inhibitors of phosphoinositide 3-kinases. J Biol Chem 284:28392–28400

    Article  CAS  Google Scholar 

  33. Cautain B, de Pedro N, Murillo Garzon V, Munoz de Escalona M, Gonzalez Menendez V, Tormo JR, Martin J, El Aouad N, Reyes F, Asensio F, Genilloud O, Vicente F, Link W (2014) High-content screening of natural products reveals novel nuclear export inhibitors. J Biomol Screen 19:57–65

    Article  CAS  Google Scholar 

  34. Zanella F, Rosado A, Garcia B, Carnero A, Link W (2009) Using multiplexed regulation of luciferase activity and GFP translocation to screen for FOXO modulators. BMC Cell Biol 10:14

    Article  Google Scholar 

  35. Zanella F, Rosado A, Garcia B, Carnero A, Link W (2008) Chemical genetic analysis of FOXO nuclear-cytoplasmic shuttling by using image-based cell screening. Chembiochem 9:2229–2237

    Article  CAS  Google Scholar 

  36. Cautain B, Castillo F, Musso L, Ferreira BI, de Pedro N, Rodriguez Quesada L, Machado S, Vicente F, Dallavalle S, Link W (2016) Discovery of a Novel, Isothiazolonaphthoquinone-based small molecule activator of FOXO nuclear-cytoplasmic shuttling. PLoS One 11:e0167491

    Article  Google Scholar 

  37. Mori M, Vignaroli G, Cau Y, Dinic J, Hill R, Rossi M, Colecchia D, Pesic M, Link W, Chiariello M, Ottmann C, Botta M (2014) Discovery of 14-3-3 protein-protein interaction inhibitors that sensitize multidrug-resistant cancer cells to doxorubicin and the Akt inhibitor GSK690693. ChemMedChem 9:973–983

    Article  CAS  Google Scholar 

  38. Cortes R, Tarrado-Castellarnau M, Talancon D, Lopez C, Link W, Ruiz D, Centelles JJ, Quirante J, Cascante M (2014) A novel cyclometallated Pt(II)-ferrocene complex induces nuclear FOXO3a localization and apoptosis and synergizes with cisplatin to inhibit lung cancer cell proliferation. Metallomics 6:622–633

    Article  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by Fundação para a Ciência e a Tecnologia (FCT) Research Center Grant UID/BIM/04773/2013 Centre for Biomedical Research 1334. Work in the laboratory of WL was funded by a research grant from Liga Portuguesa Contra o Cancro—Núcleo Regional do Sul (LPCC/NRS).

Author information

Authors and Affiliations

  1. Instituto de Investigaciones Biomédicas “Alberto Sols” (CSIC-UAM), Arturo Duperier, Madrid, Spain

    Wolfgang Link

Authors

Editor information

Editors and Affiliations

  1. Instituto de Investigaciones Biomédicas “Alberto Sols” (CSIC-UAM), Madrid, Spain

    Wolfgang Link

Rights and permissions

Reprints and permissions

Copyright information

© 2019 Springer Science+Business Media, LLC, part of Springer Nature

About this protocol

Check for updates. Verify currency and authenticity via CrossMark

Cite this protocol

Link, W. (2019). Introduction to FOXO Biology. In: Link, W. (eds) FOXO Transcription Factors. Methods in Molecular Biology, vol 1890. Humana, New York, NY. https://doi.org/10.1007/978-1-4939-8900-3_1

Download citation

  • DOI: https://doi.org/10.1007/978-1-4939-8900-3_1

  • Published:

  • Publisher Name: Humana, New York, NY

  • Print ISBN: 978-1-4939-8899-0

  • Online ISBN: 978-1-4939-8900-3

  • eBook Packages: Springer Protocols

Publish with us

Policies and ethics

Search

Navigation