Ribosomal S6 Kinase 2 Is a Key Regulator in Tumor Promoter–Induced Cell Transformation

Cho, Yong‐Yeon; Yao, Ke; Kim, Hong-Gyum; Kang, Bong Seok; Zheng, Duo; Bode, Ann M.; Dong, Zigang

doi:10.1158/0008-5472.can-06-4668

Cited by 106 publications

(140 citation statements)

References 46 publications

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“…Cell Culture, Transfection, and Treatment with EriodictyolCulture of JB6 Cl41 cells and RSK2 ϩ/ϩ and RSK2 Ϫ/Ϫ mouse embryonic fibroblasts (MEFs) was described previously (13). Transfection of the various expression vectors and luciferase reporter plasmids was conducted using jetPEI (Polyplus Transfection, New York, NY) according to the manufacturer's instructions.…”

Section: Methodsmentioning

confidence: 99%

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Eriodictyol Inhibits RSK2-ATF1 Signaling and Suppresses EGF-induced Neoplastic Cell Transformation

Liu

Cho

Yao

et al. 2011

Journal of Biological Chemistry

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RSK2 is a widely expressed serine/threonine kinase, and its activation enhances cell proliferation. Here, we report that ATF1 is a novel substrate of RSK2 and that RSK2-ATF1 signaling plays an important role in EGF-induced neoplastic cell transformation. RSK2 phosphorylated ATF1 at Ser-63 and enhanced ATF1 transcriptional activity. Docking experiments using the crystal structure of the RSK2 N-terminal kinase domain combined with in vitro pulldown assays demonstrated that eriodictyol, a flavanone found in fruits, bound with the N-terminal kinase domain of RSK2 to inhibit RSK2 N-terminal kinase activity. In cells, eriodictyol inhibited phosphorylation of ATF1 but had no effect on the phosphorylation of RSK, MEK1/2, ERK1/2, p38 or JNKs, indicating that eriodictyol specifically suppresses RSK2 signaling. Furthermore, eriodictyol inhibited RSK2-mediated ATF1 transactivation and tumor promoter-induced transformation of JB6 Cl41 cells. Eriodictyol or knockdown of RSK2 or ATF1 also suppressed Ras-mediated focus formation. Overall, these results indicate that RSK2-ATF1 signaling plays an important role in neoplastic cell transformation and that eriodictyol is a novel natural compound for suppressing RSK2 kinase activity. RSK2 (ribosomal S6 kinase 2) is a member of the p90 RSK protein family that is activated by ERK1/2 and PDK1 (phosphoinositide-dependent kinase 1) (1, 2). RSK2 translocates to the nucleus when activated by growth factors, peptide hormones, or neurotransmitters (3, 4). Numerous proteins, such as the cAMP response element (CRE) 3 -binding protein (CREB), Elk-1, histones (5-9), ATF4 (activating transcription factor 4) (10), p53 (11), and NFAT3 (12), are phosphorylated by active RSK2. Based on its broad substrate specificity, the RSK2 protein mediates many cellular processes, including proliferation and transformation, as well as the cell cycle. Our recent study provided evidence indicating that RSK2 plays an important role in cell transformation induced by tumor promoters such as EGF and 12-O-tetradecanoylphorbol-13-acetate (13). Furthermore, RSK2 knock-out mice display reduced c-Fos-dependent osteosarcoma formation through the regulation of c-Fos protein stability (14). Thus, RSK2 likely plays a key role in cell proliferation and transformation.ATF1 is a member of the CREB family, which includes ATF1, CREB1, and the CRE modulator (15). In response to growth factors, stress signals, neurotransmitters, or other agents that elevate intracellular cAMP or Ca 2ϩ levels, CREB family members are activated and promote the expression of numerous cellular target genes that contain CREs in their promoters (16), including proto-oncogenes such as c-fos and c-jun (17, 18) and cell cycle genes such as cyclins D and A and other genes related to cell growth, proliferation, and neuronal activities (19,20). Phosphorylation of ATF1 at Ser-63 in its kinase-inducible domain by serine/threonine kinases enhances its transactivation activity by promoting recruitment of the coactivator CREB-binding protein/p300 (21). ATF1 is overexpr...

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Section: Methodsmentioning

confidence: 99%

“…recent study provided evidence indicating that RSK2 plays an important role in cell transformation induced by tumor promoters such as EGF and 12-O-tetradecanoylphorbol-13-acetate (13). Furthermore, RSK2 knock-out mice display reduced c-Fos-dependent osteosarcoma formation through the regulation of c-Fos protein stability (14).…”

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confidence: 99%

Eriodictyol Inhibits RSK2-ATF1 Signaling and Suppresses EGF-induced Neoplastic Cell Transformation

Liu

Cho

Yao

et al. 2011

Journal of Biological Chemistry

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“…Their downstream substrates include a number of cytoplasmic and nuclear targets (CREB, Fos, Jun, TSC2 and filamin A (Anjum and Blenis 2008)) that explain their involvement in diverse cellular processes, such as cell proliferation and survival. Increased expression of RSKs was shown in breast and prostate cancer (Clark et al, 2005), whereas RSK2 activity has been linked to cell transformation (Cho et al, 2007;Kang et al, 2007). RSKs have been shown to phosphorylate filamin A (Woo et al, 2004) and p27Kip (Larrea et al, 2009), with RSK1 being implicated in promoting melanoma cell migration in vitro (Larrea et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

An siRNA screen identifies RSK1 as a key modulator of lung cancer metastasis

et al. 2011

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We performed a kinome-wide siRNA screen and identified 70 kinases altering cell migration in A549 lung cancer cells. In particular, ribosomal S6 kinase 1 (RSK1) silencing increased, whereas RSK2 and RSK4 downregulation inhibited cell motility. In a secondary collagenbased three-dimensional invasion screen, 38 of our hits cross-validated, including RSK1 and RSK4. In two further lung cancer cell lines, RSK1 but not RSK4 silencing showed identical modulation of cell motility. We therefore selected RSK1 for further investigation. Bioinformatic analysis followed by co-immunoprecipitation-based validation revealed that the actin regulators VASP and Mena interact with RSK1. Moreover, RSK1 phosphorylated VASP on T278, a site regulating its binding to actin. In addition, silencing of RSK1 enhanced the metastatic potential of these cells in vivo using a zebrafish model. Finally, we investigated the relevance of this finding in human lung cancer samples. In isogenically matched tissue, RSK1 was reduced in metastatic versus primary lung cancer lesions. Moreover, patients with RSK1-negative lung tumours showed increased number of metastases. Our results suggest that the findings of our high-throughput in vitro screen can reliably identify relevant clinical targets and as a proof of principle, RSK1 may provide a biomarker for metastasis in lung cancer patients.

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“…The 90 kDa ribosomal S6 kinases (RSKs) are serine/ threonine kinases and lie downstream of Ras/mitogenactivated protein kinase (MAPK) pathway, which are responsible for activating some important cellular components including transcription factors and histones [1][2][3][4][5][6][7][8] . This family consists of four human isoforms (RSK1-4) with each being a product of a separate gene 9 , among which RSK2 has attracted more attention, for its over expression and aberrant activation have been linked to many human diseases, including breast cancer, prostate cancer 10 .…”

Section: Introductionmentioning

confidence: 99%

Synthesis, activity evaluation, and docking analysis of barbituric acid aryl hydrazone derivatives as RSK2 inhibitors

Xue

Lü

et al. 2012

Journal of Enzyme Inhibition and Medicinal Chemistry

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Ribosomal S6 Kinase 2 Is a Key Regulator in Tumor Promoter–Induced Cell Transformation

Cited by 106 publications

References 46 publications

Eriodictyol Inhibits RSK2-ATF1 Signaling and Suppresses EGF-induced Neoplastic Cell Transformation

Eriodictyol Inhibits RSK2-ATF1 Signaling and Suppresses EGF-induced Neoplastic Cell Transformation

An siRNA screen identifies RSK1 as a key modulator of lung cancer metastasis

Synthesis, activity evaluation, and docking analysis of barbituric acid aryl hydrazone derivatives as RSK2 inhibitors

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