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Molecular and Cellular Biology, July 2007, p. 4917-4930, Vol. 27, No. 13
0270-7306/07/$08.00+0     doi:10.1128/MCB.01789-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Induction of Mxi1-SR{alpha} by FOXO3a Contributes to Repression of Myc-Dependent Gene Expression{triangledown} ,{dagger}

Oona Delpuech,1 Beatrice Griffiths,1 Philip East,2 Abdelkader Essafi,4 Eric W.-F. Lam,4 Boudewijn Burgering,5 Julian Downward,3 and Almut Schulze1*

Gene Expression Analysis Laboratory,1 Bioinformatics and Biostatistics Service,2 Signal Transduction Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3PX, United Kingdom,3 Cancer Research UK Labs and Department of Oncology, MRC Cyclotron Building, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 0NN, United Kingdom,4 Department of Physiological Chemistry, University Medical Center, Universiteitsweg 100, 3584CX Utrecht, The Netherlands5

Received 21 September 2006/ Returned for modification 30 October 2006/ Accepted 11 April 2007

Forkhead transcription factors of the O class (FOXOs) are important targets of the phosphatidylinositol 3-kinase (PI3-kinase)/Akt pathway. FOXOs have been implicated in the regulation of cell cycle progression, oxidative stress resistance, and apoptosis. Using DNA microarrays, we analyzed the transcriptional response to FOXO3a activation by gene expression analysis in DLD-1 colon cancer cells stably expressing a FOXO3a.A3-ER fusion protein. We found that activation of FOXO3a resulted in repression of a number of previously identified Myc target genes. Furthermore, FOXO3a activation induced expression of several members of the Mad/Mxd family of transcriptional repressors, most notably Mxi1. The induction of Mxi1 by FOXO3a was specific to the Mxi1-SR{alpha} isoform and was mediated by three highly conserved FOXO binding sites within the first intron of the gene. Activation of FOXO3a in response to inhibition of Akt also resulted in activation of Mxi1-SR{alpha} expression. Silencing of Mxi1 by small interfering RNA (siRNA) reduced FOXO3a-mediated repression of a number of Myc target genes. We also observed that FOXO3a activation induced a switch in promoter occupancy from Myc to Mxi1 on the E-box containing promoter regions of two Myc target genes, APEX and FOXM1. siRNA-mediated transient silencing of Mxi1 or all Mad/Mxd proteins reduced exit from S phase in response to FOXO3a activation, and stable silencing of Mxi1 or Mad1 reduced the growth inhibitory effect of FOXO3a. We conclude that induction of Mad/Mxd proteins contributes to the inhibition of proliferation in response to FOXO3a activation. Our results provide evidence of direct regulation of Mxi1 by FOXO3a and imply an additional mechanism through which the PI3-kinase/Akt/FOXO pathway can modulate Myc function.

* Corresponding author. Mailing address: Gene Expression Analysis Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3PX, United Kingdom. Phone: 44 20 7269 3663. Fax: 44 20 7269 3094. E-mail: almut.schulze{at}cancer.org.uk

{triangledown} Published ahead of print on 23 April 2007.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, July 2007, p. 4917-4930, Vol. 27, No. 13
0270-7306/07/$08.00+0     doi:10.1128/MCB.01789-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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