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Published online February 25, 2008
doi:10.1083/jcb.200710100
The Journal of Cell Biology, Vol. 180, No. 4, 691-696
The Rockefeller University Press, 0021-9525 $30.00
© 2008 Harvey et al.
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Report

 FOXO-regulated transcription restricts overgrowth of Tsc mutant organs

Kieran F. Harvey1,2,5, Jaakko Mattila3, Avi Sofer4, F. Christian Bennett1,2, Matthew R. Ramsey4, Leif W. Ellisen4, Oscar Puig3, and Iswar K. Hariharan5

1 Cell Growth and Proliferation Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia
2 Department of Pathology, University of Melbourne, Parkville, Victoria 3010, Australia
3 Institute of Biotechnology, University of Helsinki, Helsinki 00014, Finland
4 Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114
5 Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720

Correspondence to K.F. Harvey: kieran.harvey{at}petermac.org

FOXO is thought to function as a repressor of growth that is, in turn, inhibited by insulin signaling. However, inactivating mutations in Drosophila melanogaster FOXO result in viable flies of normal size, which raises a question over the involvement of FOXO in growth regulation. Previously, a growth-suppressive role for FOXO under conditions of increased target of rapamycin (TOR) pathway activity was described. Here, we further characterize this phenomenon. We show that tuberous sclerosis complex 1 mutations cause increased FOXO levels, resulting in elevated expression of FOXO-regulated genes, some of which are known to antagonize growth-promoting pathways. Analogous transcriptional changes are observed in mammalian cells, which implies that FOXO attenuates TOR-driven growth in diverse species.

Abbreviations used in this paper: chrb, charybdis; FRE, FOXO recognition element; FRT, flipase recognition target; GMR, glass multiple reporter; GOF, gain of function; HIF-1, hypoxia-inducible factor-1; hsp, heat shock protein; LOF, loss of function; MEF, mouse embryonic fibroblast; QPCR, quantitative real-time PCR; scy, scylla; tgo, tango; TOR, target of rapamycin; TSC, tuberous sclerosis complex.


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