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Molecular and Cellular Biology, July 2003, p. 4417-4427, Vol. 23, No. 13
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.13.4417-4427.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Akt Regulates Basic Helix-Loop-Helix Transcription Factor-Coactivator Complex Formation and Activity during Neuronal Differentiation

Anne B. Vojtek,1* Jennifer Taylor,1 Stacy L. DeRuiter,2 Jenn-Yah Yu,2,3 Claudia Figueroa,1 Roland P. S. Kwok,1,4 and David L. Turner1,2,3*

Department of Biological Chemistry,1 Mental Health Research Institute,2 Program in Neuroscience,3 Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, Michigan4

Received 27 December 2002/ Returned for modification 18 February 2003/ Accepted 16 April 2003

Neural basic helix-loop-helix (bHLH) transcription factors regulate neurogenesis in vertebrates. Signaling by peptide growth factors also plays critical roles in regulating neuronal differentiation and survival. Many peptide growth factors activate phosphatidylinositol 3-kinase (PI3K) and subsequently the Akt kinases, raising the possibility that Akt may impact bHLH protein function during neurogenesis. Here we demonstrate that reducing expression of endogenous Akt1 and Akt2 by RNA interference (RNAi) reduces neuron generation in P19 cells transfected with a neural bHLH expression vector. The reduction in neuron generation from decreased Akt expression is not solely due to decreased cell survival, since addition of the caspase inhibitor z-VAD-FMK rescues cell death associated with loss of Akt function but does not restore neuron formation. This result indicates that Akt1 and Akt2 have additional functions during neuronal differentiation that are separable from neuronal survival. We show that activated Akt1 enhances complex formation between bHLH proteins and the transcriptional coactivator p300. Activated Akt1 also significantly augments the transcriptional activity of the bHLH protein neurogenin 3 in complex with the coactivators p300 or CBP. In addition, inhibition of endogenous Akt activity by the PI3K/Akt inhibitor LY294002 abolishes transcriptional cooperativity between the bHLH proteins and p300. We propose that Akt regulates the assembly and activity of bHLH-coactivator complexes to promote neuronal differentiation.

* Corresponding author. Mailing address for Anne B. Vojtek: Department of Biological Chemistry, University of Michigan, 3323 MSRB III Box 0606, Ann Arbor, MI 48109-0606. Phone: (734) 647-6794. Fax: (734) 763-7799. E-mail: avojtek{at}umich.edu or dlturner{at}umich.edu.

Molecular and Cellular Biology, July 2003, p. 4417-4427, Vol. 23, No. 13
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.13.4417-4427.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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