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Coordinate regulation of forskolin-induced cellular proliferation in macrophages by protein kinase A/cAMP-response element-binding protein (CREB) and Epac1-Rap1 signaling: effects of silencing CREB gene expression on Akt activation.
J Biol Chem. 2005 Nov 18; 280(46):38276-89.JB

Abstract

In this study, we have examined the role of two cAMP downstream effectors protein kinase A (PKA) and Epac, in forskolin-induced macrophage proliferation. Treatment of macrophages with forskolin enhanced [(3)H]thymidine uptake and increased cell number, and both were profoundly reduced by prior treatment of cells with H-89, a specific PKA inhibitor. Incubation of macrophages with forskolin triggered the activation of Akt, predominantly by phosphorylation of Ser-473, as measured by Western blotting and assay of its kinase activity. Akt activation was significantly inhibited by LY294002 and wortmannin, specific inhibitors of phosphatidylinositol 3-kinase, but not by H-89. Incubation of macrophages with forskolin also increased Epac1 and Rap1.GTP. Immunoprecipitation of Epac1 in forskolin-stimulated cells co-immunoprecipitated Rap1, p-Akt(Thr-308), and p-Akt(Ser-473). Silencing of CREB gene expression by RNA interference prior to forskolin treatment not only decreased CREB protein and its phosphorylation at Ser-133, but also phosphorylation of Akt at Ser-473, and Thr-308. Concomitantly, this treatment inhibited [(3)H]thymidine uptake and reduced forskolin-induced proliferation of macrophages. Forskolin treatment also inhibited activation of the apoptotic mechanism while promoting up-regulation of the anti-apoptotic pathway. We conclude that forskolin mediates cellular proliferation via cAMP-dependent activation of both PKA and Epac.

Authors+Show Affiliations

Department of Pathology, Duke University, Medical Center, Durham, North Carolina 27710, USA.No affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

16172130

Citation

Misra, Uma K., and Salvatore V. Pizzo. "Coordinate Regulation of Forskolin-induced Cellular Proliferation in Macrophages By Protein Kinase A/cAMP-response Element-binding Protein (CREB) and Epac1-Rap1 Signaling: Effects of Silencing CREB Gene Expression On Akt Activation." The Journal of Biological Chemistry, vol. 280, no. 46, 2005, pp. 38276-89.
Misra UK, Pizzo SV. Coordinate regulation of forskolin-induced cellular proliferation in macrophages by protein kinase A/cAMP-response element-binding protein (CREB) and Epac1-Rap1 signaling: effects of silencing CREB gene expression on Akt activation. J Biol Chem. 2005;280(46):38276-89.
Misra, U. K., & Pizzo, S. V. (2005). Coordinate regulation of forskolin-induced cellular proliferation in macrophages by protein kinase A/cAMP-response element-binding protein (CREB) and Epac1-Rap1 signaling: effects of silencing CREB gene expression on Akt activation. The Journal of Biological Chemistry, 280(46), 38276-89.
Misra UK, Pizzo SV. Coordinate Regulation of Forskolin-induced Cellular Proliferation in Macrophages By Protein Kinase A/cAMP-response Element-binding Protein (CREB) and Epac1-Rap1 Signaling: Effects of Silencing CREB Gene Expression On Akt Activation. J Biol Chem. 2005 Nov 18;280(46):38276-89. PubMed PMID: 16172130.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Coordinate regulation of forskolin-induced cellular proliferation in macrophages by protein kinase A/cAMP-response element-binding protein (CREB) and Epac1-Rap1 signaling: effects of silencing CREB gene expression on Akt activation. AU - Misra,Uma K, AU - Pizzo,Salvatore V, Y1 - 2005/09/19/ PY - 2005/9/21/pubmed PY - 2006/1/13/medline PY - 2005/9/21/entrez SP - 38276 EP - 89 JF - The Journal of biological chemistry JO - J Biol Chem VL - 280 IS - 46 N2 - In this study, we have examined the role of two cAMP downstream effectors protein kinase A (PKA) and Epac, in forskolin-induced macrophage proliferation. Treatment of macrophages with forskolin enhanced [(3)H]thymidine uptake and increased cell number, and both were profoundly reduced by prior treatment of cells with H-89, a specific PKA inhibitor. Incubation of macrophages with forskolin triggered the activation of Akt, predominantly by phosphorylation of Ser-473, as measured by Western blotting and assay of its kinase activity. Akt activation was significantly inhibited by LY294002 and wortmannin, specific inhibitors of phosphatidylinositol 3-kinase, but not by H-89. Incubation of macrophages with forskolin also increased Epac1 and Rap1.GTP. Immunoprecipitation of Epac1 in forskolin-stimulated cells co-immunoprecipitated Rap1, p-Akt(Thr-308), and p-Akt(Ser-473). Silencing of CREB gene expression by RNA interference prior to forskolin treatment not only decreased CREB protein and its phosphorylation at Ser-133, but also phosphorylation of Akt at Ser-473, and Thr-308. Concomitantly, this treatment inhibited [(3)H]thymidine uptake and reduced forskolin-induced proliferation of macrophages. Forskolin treatment also inhibited activation of the apoptotic mechanism while promoting up-regulation of the anti-apoptotic pathway. We conclude that forskolin mediates cellular proliferation via cAMP-dependent activation of both PKA and Epac. SN - 0021-9258 UR - https://www.unboundmedicine.com/medline/citation/16172130/Coordinate_regulation_of_forskolin_induced_cellular_proliferation_in_macrophages_by_protein_kinase_A/cAMP_response_element_binding_protein__CREB__and_Epac1_Rap1_signaling:_effects_of_silencing_CREB_gene_expression_on_Akt_activation_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0021-9258(19)37688-4 DB - PRIME DP - Unbound Medicine ER -