A-kinase-interacting protein 1 (AKIP1) acts as a molecular determinant of PKA in NF-kappaB signaling.

Abstract

The cAMP-dependent protein kinase (PKA) signaling pathway plays a crucial role in the pathogenesis of many NF-kappaB-related diseases. However, there have been controversial reports with regard to the PKA actions in the regulation of NF-kappaB activity. In this study, we have demonstrated the effect of PKA on NF-kappaB activity in view of AKIP1 action; and in 293 and HeLa cells, where the endogenous AKIP1 expression is minimal, PKA-activating agents inhibited the NF-kappaB-dependent reporter gene expression, blocked the interaction of PKAc and p65 subunit of NF-kappaB, and attenuated PKA-dependent phosphorylation of p65 on Ser-276. This inhibitory function of PKAc in NF-kappaB signaling was reversed by overexpression of AKIP1 in 293 cells. In the breast cancer cell line, MDA-MB231 cells and MCF7 cells, where the endogenous AKIP1 is abundant, the PKA signal was found to be synergized with NF-kappaB activation; PKA-activating agents enhanced NF-kappaB-dependent transcriptional activity and the interaction between p65 and PKAc and augmented the phosphorylation of p65 on Ser-276. After RNAi knockdown of AKIP1 in these breast cancer cells, we observed that PKA-activating agents antagonized NF-kappaB-dependent activation. Meanwhile, PKA inhibitor suppressed NF-kappaB-induced breast cancer cell proliferation and multiple NF-kappaB-dependent anti-apoptotic gene expression. It is likely that expression of AKIP1 determines the relationship between these two signal transduction pathways. These findings explained controversial results from various independent groups regarding the action of PKA signaling on the NF-kappaB activation cascade and suggested a possible therapeutic potential of PKA inhibitor in developing anti-cancer strategies.

• Authors: Nan Gao, Yurina Hibi, Marni Cueno, Kaori Asamitsu, Takashi Okamoto
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 285 Issue 36 Pg. 28097-104 (Sep 03 2010) ISSN: 1083-351X [Electronic] United States
• PMID: 20562110 (Publication Type: Journal Article)

Chemical References

• AKIP1 protein, human
• Adaptor Proteins, Signal Transducing
• Neoplasm Proteins
• Nuclear Proteins
• Protein Kinase Inhibitors
• Transcription Factor RelA
• Serine
• Cyclic AMP
• CREB-Binding Protein
• CREBBP protein, human
• Cyclic AMP-Dependent Protein Kinase Catalytic Subunits

Topics

• Adaptor Proteins, Signal Transducing
• Apoptosis (genetics)
• Breast Neoplasms (pathology)
• CREB-Binding Protein (metabolism)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cyclic AMP (metabolism)
• Cyclic AMP-Dependent Protein Kinase Catalytic Subunits (antagonists & inhibitors, metabolism)
• Down-Regulation (drug effects)
• Enzyme Activation (drug effects)
• Gene Expression Regulation
• Humans
• Neoplasm Proteins (metabolism)
• Nuclear Proteins (metabolism)
• Phosphorylation (drug effects)
• Protein Kinase Inhibitors (pharmacology)
• Serine (metabolism)
• Signal Transduction
• Transcription Factor RelA (chemistry, metabolism)
• Transcription, Genetic (drug effects)