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首页> 外文期刊>Molecular and Cellular Biology >Stimulation of GCMa Transcriptional Activity by Cyclic AMP/Protein Kinase A Signaling Is Attributed to CBP-Mediated Acetylation of GCMa
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Stimulation of GCMa Transcriptional Activity by Cyclic AMP/Protein Kinase A Signaling Is Attributed to CBP-Mediated Acetylation of GCMa

机译：循环AMP /蛋白质激酶A刺激GCMa转录活性的信号归因于CBP介导的GCMa乙酰化

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摘要

Human GCMa is a zinc-containing transcription factor primarily expressed in placenta. GCMa regulates expression of syncytin gene, which encodes for a placenta-specific membrane protein that mediates trophoblastic fusion and the formation of syncytiotrophoblast layer required for efficient fetal-maternal exchange of nutrients and oxygen. The adenylate cyclase activator, forskolin, stimulates syncytin gene expression and cell fusion in cultured placental cells. Here we present evidence that cyclic AMP (cAMP) signaling pathway activates the syncytin gene expression by regulating GCMa activity. We found that forskolin and protein kinase A (PKA) enhances GCMa-mediated transcriptional activation. Furthermore, PKA treatment stimulates the association of GCMa with CBP and increases GCMa acetylation. CBP primarily acetylates GCMa at lysine367, lysine406, and lysine409 in the transactivation domain (TAD). We found that acetylation of these residues is required to protect GCMa from ubiquitination and increases the TAD stability with a concomitant increase in transcriptional activity, supporting the importance of acetylation in PKA-dependent GCMa activation. Our results reveal a novel regulation of GCMa activity by cAMP-dependent protein acetylation and provide a molecular mechanism by which cAMP signaling regulates trophoblastic fusion.
机译：人GCMa是主要在胎盘中表达的含锌转录因子。 GCMa调节 syncytin 基因的表达，该基因编码胎盘特异性膜蛋白，该蛋白介导滋养层融合和形成胎儿-母体有效交换养分和氧气所需的合胞体滋养层。腺苷酸环化酶激活剂forskolin在培养的胎盘细胞中刺激 syncytin 基因表达和细胞融合。在这里，我们提供了证据，表明环AMP（cAMP）信号通路通过调节GCMa活性激活 syncytin 基因表达。我们发现毛喉素和蛋白激酶A（PKA）增强了GCMa介导的转录激活。此外，PKA处理刺激了GCMa与CBP的缔合并增加了GCMa的乙酰化。 CBP主要在反式激活域（TAD）中的赖氨酸 367 ，赖氨酸 406 和赖氨酸 409 处乙酰化GCMa。我们发现这些残基的乙酰化是保护GCMa免受泛素化所必需的，并增加了TAD的稳定性，同时伴随转录活性的增加，支持了乙酰化在PKA依赖性GCMa激活中的重要性。我们的结果揭示了cAMP依赖性蛋白乙酰化对GCMa活性的新调节，并提供了cAMP信号传导调节滋养细胞融合的分子机制。

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