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Molecular and Cellular Biology, September 2009, p. 4878-4890, Vol. 29, No. 18
0270-7306/09/$08.00+0     doi:10.1128/MCB.01928-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Time-Dependent Activation of Phox2a by the Cyclic AMP Pathway Modulates Onset and Duration of p27Kip1 Transcription{triangledown} ,{dagger}

Min Hwa Shin,1,3 Nirmala Mavila,1,3 Wen-Horng Wang,1,3 Sasha Vega Alvarez,1,3 Mark C. Hall,2,3 and Ourania M. Andrisani1,3*

Department of Basic Medical Sciences,1 Department of Biochemistry,2 Center for Cancer Research, Purdue University, West Lafayette, Indiana 479073

Received 19 December 2008/ Returned for modification 1 February 2009/ Accepted 18 June 2009

In noradrenergic progenitors, Phox2a mediates cell cycle exit and neuronal differentiation by inducing p27Kip1 transcription in response to activation of the cyclic AMP (cAMP) pathway. The mechanism of cAMP-mediated activation of Phox2a is unknown. We identified a cluster of phosphoserine-proline sites in Phox2a by mass spectrometry. Ser206 appeared to be the most prominent phosphorylation site. A phospho-Ser206 Phox2a antibody detected dephosphorylation of Phox2a that was dependent on activation of the cAMP pathway, which occurred prior to neuronal differentiation of noradrenergic CAD cells. Employing serine-to-alanine and serine-to-aspartic acid Phox2a substitution mutants expressed in inducible CAD cell lines, we demonstrated that the transcriptional activity of Phox2a is regulated by two sequential cAMP-dependent events: first, cAMP signaling promotes dephosphorylation of Phox2a in at least one site, Ser206, thereby allowing Phox2a to bind DNA and initiate p27Kip1 transcription; second, following dephosphorylation of the phosphoserine cluster (Ser202 and Ser208), Phox2a becomes phosphorylated by protein kinase A (PKA) on Ser153, which prevents association of Phox2a with DNA and terminates p27Kip1 transcription. This represents a novel mechanism by which the same stimulus, cAMP signaling, first activates Phox2a by dephosphorylation of Ser206 and then, after a built-in delay, inactivates Phox2a via PKA-dependent phosphorylation of Ser153, thereby modulating onset and duration of p27Kip1 transcription.

* Corresponding author. Mailing address: Department of Basic Medical Sciences, Purdue University, 625 Harrison Street, West Lafayette, IN 47907-2026. Phone: (765) 494-8131. Fax: (765) 494-0781. E-mail: andrisao{at}purdue.edu

{triangledown} Published ahead of print on 29 June 2009.

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

Molecular and Cellular Biology, September 2009, p. 4878-4890, Vol. 29, No. 18
0270-7306/09/$08.00+0     doi:10.1128/MCB.01928-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Eiden, L. E. (2009). Timing the Phox-Trot: Duration of Phox2a-Dependent Transcription Is Controlled by an Intramolecular Dephosphorylation/Phosphorylation Clock. Mol. Cell. Biol. 29: 4875-4877 [Full Text]  


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