RGS19 upregulates Nm23-H1/2 metastasis suppressors by transcriptional activation via the cAMP/PKA/CREB pathway
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Yuanjun Li1, Jiaxing Song1, Yao Tong1, Sookja Kim Chung2 and Yung H. Wong1,3,4
1Division of Life Sciences and the Biotechnology Research Institute, Hong Kong University of Science and Technology, Hong Kong, China
2School of Biomedical Sciences, University of Hong Kong, Hong Kong, China
3State Key Laboratory of Molecular Neuroscience and the Molecular Neuroscience Center, Hong Kong University of Science and Technology, Hong Kong, China
4Guangdong Provincial Key Laboratory of Brain Science, Disease and Drug Development, HKUST Shenzhen Research Institute, Shenzhen, China
Yung H. Wong, email: [email protected]
Keywords: Nm23, RGS19, transcriptional regulation, PKA
Received: December 15, 2016 Accepted: June 20, 2017 Published: July 22, 2017
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.
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