Editors' ChoiceBiochemistry

More Regulation for FOXO

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Science's STKE  10 Oct 2006:
Vol. 2006, Issue 356, pp. tw346
DOI: 10.1126/stke.3562006tw346

The FOXO (Forkhead box O) transcription factors are implicated in control of stress responses, cell death, aging, and tumor suppression, so perhaps it is no surprise that they are subject to multiple layers of regulation. Key targets of protein kinase B, they are also regulated by acetylation (which appears to enhance or suppress transcriptional activity, depending on the site of acetylation) and polyubiquitination (the covalent addition of multiple ubiquitin polypeptides). Van der Horst et al. now report that FOXO4 is also regulated by monoubiquitination, which--unlike polyubiquitination, which often targets proteins for degradation--often has other signaling roles. The authors show that in human embryonic kidney 293T cells expressing tagged FOXO4 and ubiquitin molecules, oxidative stress brought about by incubation of cells with hydrogen peroxide caused increased monoubiquitination of FOXO4. A fluorescence complementation assay in which part of the yellow fluorescent protein was tacked on to ubiquitin and part onto FOXO4 revealed nuclear or perinuclear localization of the ubiquitinated protein (detected when the parts of the fluorescent protein come together). Analysis of a FOXO-responsive reporter gene showed that expression of a FOXO4-ubiquitin fusion protein (that mimics monoubiquitinated FOXO) increased transcriptional activation by FOXO4. A search for proteins associated with the deubiquitinating enzyme (DUB) USP7 (also called HAUSP, for herpes virus-associated ubiquitin-specific protease) independently turned up FOXO4. Overexpression of USP7 or depletion of the protein by RNA interference caused decreased or increased FOXO transcriptional activity, respectively. The authors propose that the regulation of FOXO4 by USP7 might provide a new therapeutic strategy against cancer to complement current efforts to antagonize signals from protein kinase B. Furthermore, they note that there is remarkable similarity in the regulatory mechanisms controlling FOXO4 with those regulating the p53 tumor suppressor protein, better understanding of which promises to shed light on mechanisms of aging in mammals. Huang and D’Andrea provide commentary.

A. van der Horst, A. M. M. de Vries-Smits, A. B. Brenkman, M. H. van Triest, N. van den Broek, F. Colland, M. M. Maurice, B. M. T. Burgering, FOXO4transcriptional activity is regulated by monoubiquitination and USP7/HAUSP. Nat. Cell Biol. 8, 1064-1073 (2006). [PubMed]

T. T. Huang, A. D. D’Andrea, HAUSP hunting the FOX(O). Nat. Cell Biol. 8, 1043-1045 (2006). [PubMed]

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