Cytoplasmic catalytic subunit of protein kinase A mediates cross-repression by NF-κB and the glucocorticoid receptor
Cytoplasmic catalytic subunit of protein kinase A mediates cross-repression by NF-κB and the glucocorticoid receptor
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DOI：
10.1073/pnas.220413297
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发表时间：
2000-10-24
影响因子：
11.1
通讯作者：
Evans, RM
中科院分区：
文献类型：
--
作者：
Doucas, V;Shi, YH;Evans, RM
NF-κ B（RelA）和糖皮质激素受体（CR）之间的负转录调节或交叉偶联被认为在人类生理和疾病中起调节作用。尽管之前有进步。这种现象的生物化学基础仍然是一个有争议的问题。我们在这里表明，GR活性的抑制RelA不需要RelA DNA结合，反式激活，或核定位域。令人惊讶的是，RelA阻遏上废除的保守的蛋白激酶A（PKA）的氨基酸残基276的RelA位点的突变，我们表明，CR协会在体内和体外与PKA（PKAc）的催化亚基在配体非依赖性的方式和GR转录依赖于PKA信号。事实上，我们证明GR介导的NF-κ B反式激活抑制是PKAc依赖性的。与以前的模型相比，我们认为交叉偶联需要一个细胞质步骤，并受PKAc相关信号的调节。
Negative transcriptional regulation or cross-coupling between NF-kappaB (RelA) and the glucocorticoid receptor (CR) is proposed to play a regulatory role in human physiology and disease. Despite previous advances. the biochemical basis of this phenomenon remains a subject of controversy. We show here that the inhibition of GR activity by RelA does not require the RelA DNA binding, transactivation, or nuclear localization domains. Surprisingly, RelA repression of on is abolished by mutation of the conserved protein kinase A (PKA) site at amino acid residue 276 of RelA, We show that CR associates in vivo and in vitro with the catalytic subunit of PKA (PKAc) in a ligand-independent manner and that GR transcription depends on PKA signaling. Indeed, we demonstrated that GR-mediated inhibition of NF-kappaB transactivation is PKAc-dependent. In contrast to previous models, we suggest that the cross-coupling requires a cytoplasmic step and is regulated by a PKAc-associated signaling.