A-kinase-interacting Protein 1 (AKIP1) Acts as a Molecular Determinant of PKA in NF-κB Signaling

被引:68
作者
Gao, Nan [1 ]
Hibi, Yurina [1 ]
Cueno, Marni [1 ]
Asamitsu, Kaori [1 ]
Okamoto, Takashi [1 ]
机构
[1] Nagoya City Univ, Grad Sch Med Sci, Dept Mol & Cellular Biol, Mizuho Ku, Nagoya, Aichi 4678601, Japan
关键词
BREAST-CANCER CELLS; MULTIPLE-MYELOMA CELLS; TRANSCRIPTIONAL ACTIVITY; ENDOTHELIAL-CELLS; SERINE KINASE; ACTIVATION; PHOSPHORYLATION; PATHWAY; ALPHA; P65;
D O I
10.1074/jbc.M110.116566
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The cAMP-dependent protein kinase (PKA) signaling pathway plays a crucial role in the pathogenesis of many NF-kappa B-related diseases. However, there have been controversial reports with regard to the PKA actions in the regulation of NF-kappa B activity. In this study, we have demonstrated the effect of PKA on NF-kappa B 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-kappa B-dependent reporter gene expression, blocked the interaction of PKAc and p65 subunit of NF-kappa B, and attenuated PKA-dependent phosphorylation of p65 on Ser-276. This inhibitory function of PKAc in NF-kappa B 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-kappa B activation; PKA-activating agents enhanced NF-kappa B-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-kappa B-dependent activation. Meanwhile, PKA inhibitor suppressed NF-kappa B-induced breast cancer cell proliferation and multiple NF-kappa B-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-kappa B activation cascade and suggested a possible therapeutic potential of PKA inhibitor in developing anti-cancer strategies.
引用
收藏
页码:28097 / 28104
页数:8
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