RGS19 upregulates Nm23-H1/2 metastasis suppressors by transcriptional activation via the cAMP/PKA/CREB pathway.
RGS19 upregulates Nm23-H1/2 metastasis suppressors by transcriptional activation via the cAMP/PKA/CREB pathway.
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DOI：
10.18632/oncotarget.19509
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发表时间：
2017-09-19
期刊：
影响因子：
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通讯作者：
Wong YH
中科院分区：
文献类型：
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作者：
Li Y;Song J;Tong Y;Chung SK;Wong YH
Nm23转移抑制因子家族参与包括肿瘤发生和转移在内的生理和病理过程。尽管Nm23水平与肿瘤转移潜力的负相关已被广泛观察到，但调节Nm23表达的机制仍知之甚少。我们之前的研究表明，Nm23-H1/2 亚型被 RGS19 上调，RGS19 是 G 蛋白信号传导 (RGS) 蛋白的调节因子，可加速 Gi 信号的终止。在这里，我们通过筛选一组荧光素酶报告基因来检查 RGS19 刺激 Nm23 转录调控的能力。 RGS19 的瞬时和稳定过表达上调 Nm23-H1/2 蛋白水平，并激活 HEK293 细胞中的多种转录因子，包括 CREB、AP-1 和 SRE。有趣的是，增加细胞内 cAMP 水平和 CREB 磷酸化的药物（例如肾上腺素受体激动剂、毛喉素和 cAMP 类似物）上调 HEK293 细胞和几种癌细胞系（包括 A549、HeLa、MDA-MB-231 和 MDA-MB-435s 细胞）中 Nm23-H1/2 的表达。相反，H-89 对蛋白激酶 A (PKA) 的抑制抑制了 CREB 的磷酸化并减少了 Nm23-H1/2 的表达。此外，PKA 的激活减弱了伤口愈合和 Transwell 实验中癌细胞的迁移。总的来说，这些结果揭示了控制 Nm23-H1/2 表达的 PKA 依赖性机制。
The Nm23 metastasis suppressor family is involved in physiological and pathological processes including tumorigenesis and metastasis. Although the inverse correlation of Nm23 level with tumor metastasis potential has been widely observed, the mechanisms that regulate the expression of Nm23 remain poorly understood. Our previous studies have revealed that Nm23-H1/2 isoforms are upregulated by RGS19, a regulator of G protein signaling (RGS) protein which accelerates the termination of Gi signals. Here, we examined the ability of RGS19 to stimulate transcriptional regulation of Nm23 by screening a panel of luciferase reporter genes. Transient and stable overexpression of RGS19 upregulated the Nm23-H1/2 protein levels and activated several transcription factors including CREB, AP-1 and SRE in HEK293 cells. Interestingly, agents that increase the intracellular cAMP level and the phosphorylation of CREB (e.g., adrenergic receptor agonist, forskolin, and cAMP analogues) upregulated the expression of Nm23-H1/2 in HEK293 cells and several cancer cell lines including A549, HeLa, MDA-MB-231, and MDA-MB-435s cells. Conversely, inhibition of protein kinase A (PKA) by H-89 suppressed the phosphorylation of CREB and reduced the expression of Nm23-H1/2. Furthermore, activation of PKA attenuated cancer cell migration in wound healing and transwell assays. Collectively, these results revealed a PKA-dependent mechanism for controlling Nm23-H1/2 expression.