Time-Dependent Activation of Phox2a by the Cyclic AMP Pathway Modulates Onset and Duration of p27Kip1 Transcription
Open accessAbstract
In noradrenergic progenitors, Phox2a mediates cell cycle exit and neuronal differentiation by inducing p27(Kip1) 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 p27(Kip1) 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 p27(Kip1) 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 p27(Kip1) transcription.
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The genes chosen for expression analysis have all recently been implicated in antidepressant drug action and neurogenesis.
“These genes were chosen because they have all recently been implicated in antidepressant drug action and neurogenesis.35, 36, 37, 38, 39, 12, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49”
From Antidepressants increase human hippocampal neurogenesis by activating the glucocorticoid receptor (2011) · cites this paper as [38]
p27Kip1 and p57Kip2 are GR-target genes that promote cell cycle exit and increase neuronal differentiation in the developing rat brain.
“p27Kip1 and p57Kip2 are GR-target genes that promote cell cycle exit and increase neuronal differentiation in the developing rat brain.39, 38, 69”
From Antidepressants increase human hippocampal neurogenesis by activating the glucocorticoid receptor (2011) · cites this paper as [38]
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- Authors
- Shin, M. H., Mavila, N., Wang, W.-H., Vega Alvarez, S., Hall, M. C., & Andrisani, O. M.
- Affiliations
- Purdue University West Lafayette (US)
- Department of Basic Medical Sciences
- Corresponding author
- Andrisani, Ourania M.
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2009-09-01
- Volume
- 29
- Issue
- 18
- Pages
- 4878-4890
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC2738275
- OpenAlex
- W2146451974
- Cited by
- 14
- References
- 43
- Citations by year
- 2024: 1 · 2022: 1 · 2020: 1 · 2016: 2 · 2014: 1 · 2013: 1
- FWCI
- 0.94
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular and Cellular Biology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (DK 059367, R01DK059367)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Keywords
- Phox2a, p27, cAMP signaling, protein kinase A, serine phosphorylation, transcriptional regulation, neuronal differentiation, cell cycle exit, transcription termination
- MeSH terms
- Cyclic AMP, Alanine, Amino Acid Sequence, Cell Differentiation, Cell Line, DNA, Gene Expression Regulation, Intermediate Filament Proteins, Membrane Glycoproteins, Models, Biological, Molecular Sequence Data, Nerve Tissue Proteins, Neurons, Phosphorylation, Phosphoserine, Protein Binding, RNA, Messenger, Mass Spectrometry, Time Factors, Transcription, Genetic, Signal Transduction, Cyclic AMP-Dependent Protein Kinases, Homeodomain Proteins, Amino Acid Substitution, Chromatin Immunoprecipitation, Cyclin-Dependent Kinase Inhibitor p27, Peripherins
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