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CREB Recruited to the Promoter by NO

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Science's STKE  31 Jan 2006:
Vol. 2006, Issue 320, pp. tw42
DOI: 10.1126/stke.3202006tw42

The transcription factor CREB (cAMP response element-binding protein) plays an important role in regulating neuronal gene expression in response to neurotrophins and synaptic activity. The current model is that CREB is constitutively bound at target gene promoters and activity is regulated by phosphorylation at Ser133. Riccio et al. used chromatin immunoprecipitation (ChIP) experiments (previous reports were based on electrophoretic mobility shift assays) to show that, in unstimulated cortical neurons, CREB was not bound to three target gene promoters but that brain-derived neurotrophic factor (BDNF) stimulated both the association of CREB with the promoters and CREB phosphorylation. The binding of CREB to target promoters occurred even in the presence of a pharmacological inhibitor of the mitogen-activated protein kinase (MAPK) pathway that stimulates CREB phosphorylation. Furthermore, both a nonphosphorylatable mutant of CREB and a phosphorylation mimic of CREB exhibited the same BDNF-induced association with DNA. BDNF is known to stimulate the activity of nitric oxide synthase (NOS). Pharmacological inhibition of NOS prevented BDNF-stimulated CREB binding to target gene promoters, whereas NO donors stimulated CREB binding to the promoters in the absence of BDNF and augmented BDNF-induced expression of the CREB target gene c-fos. CREB phosphorylation in response to BDNF was unchanged in mice deficient for nNOS (neuronal NOS). However, the activity-induced activation of CREB target genes (c-fos and zif-268) was decreased in the brains of mice deficient for nNOS. Histone deacetylase 2 (HDAC2), which was constitutively associated with CREB target gene promoters, was displaced from these promoters in response to BDNF, and this was prevented by addition of inhibitors of NOS activity. Thus, the authors suggest that BDNF acts through multiple pathways to stimulate recruitment of CREB to target gene promoters (by NO signaling) and phosphorylation of CREB (by MAPK signaling).

A. Riccio, R. S. Alvania, B. E. Lonze, N. Ramanan, T. Kim, Y. Huang, T. M. Dawson, S. H. Snyder, D. D. Ginty, A nitric oxide signaling pathway controls CREB-mediated gene expression in neurons. Mol. Cell 21, 283-294 (2006). [PubMed]

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