Current Drug Targets

Francis J. Castellino
Kleiderer-Pezold Professor of Biochemistry
Director, W.M. Keck Center for Transgene Research
Dean Emeritus, College of Science
230 Raclin-Carmichael Hall, University of Notre Dame
Notre Dame, IN 46556


The Complex Biology of FOXO

Author(s): Maria Monsalve and Yolanda Olmos

Affiliation: Centro Nacional de Investigaciones Cardiovasculares, Melchor Fernandez Almagro 3, Room S2. 28029-Madrid, Spain.


FOXO transcription factors control proliferation, apoptosis, differentiation and metabolic processes. Loss of FOXO function has been identified in several human cancers, and results in increased cellular survival and a predisposition to neoplasia, especially in epithelial cancer. FOXO factors are therefore bona fide tumor suppressors, and their potential use as therapeutic targets in cancer has been a matter of debate. Importantly, FOXO factors can also positively regulate cell survival through the activation of several detoxification genes, complicating its putative therapeutic potential. Targeting of FOXO factors has also been proposed for the treatment of metabolic dysfunctions such as diabetes mellitus, immunological disorders and neurodegeneration, as well as for the prevention of aging by maintaining the hematopoyetic stem cells niche. But again, data has accumulated that cautions against the potential use of the FOXO activators in these settings. Therefore, greater understanding of the regulation of FOXO target specificity is still needed to boost its use as a therapeutic target.

The four members of the FOXO family (FOXO1, FOXO3A, FOXO4 and FOXO6) have distinct but overlapping cellular functions, although they seem to bind a common set of DNA sites. This fact together with the observation that FOXOs are only partially dependent on their DNA binding activity to regulate their target genes highlights the fact that the interaction of the FOXOs with other transcription factors is crucial for the FOXO-mediated transcriptional programs.

In this review, we provide an overview of recent progress in the understanding of the modulation of FOXO activity and target specificity by transcription factors and coactivators.

Keywords: FOXO, insulin signaling, transcription factor, coactivator, metabolism, cell cycle, cell differentiation, cancer, Drosophila, Gluconeogenesesis, HNF-4, PDK4, Muscle Atrophy, SirT1, Wnt signaling, Myocardin, Smad, KLF5, EBPbeta, HoxA, PPARs, c-myc, STAT3, RUNX, TRIB2, Pin1

Order Reprints Order Eprints Rights & PermissionsPrintExport

Article Details

Page: [1322 - 1350]
Pages: 29
DOI: 10.2174/138945011796150307