title: Eriodictyol inhibits RSK2-ATF1 signaling and suppresses EGF-induced neoplastic cell transformation.
abstract: 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.
authors.affiliation: Hormel Institute, University of Minnesota, Austin, Minnesota 55912, USA.
authors.forename: Kangdong
authors.initials: K
authors.lastname: Liu
authors.forename: Yong-Yeon
authors.initials: YY
authors.lastname: Cho
authors.forename: Ke
authors.initials: K
authors.lastname: Yao
authors.forename: Janos
authors.initials: J
authors.lastname: Nadas
authors.forename: Dong Joon
authors.initials: DJ
authors.lastname: Kim
authors.forename: Eun-Jin
authors.initials: EJ
authors.lastname: Cho
authors.forename: Mee-Hyun
authors.initials: MH
authors.lastname: Lee
authors.forename: Angelo
authors.initials: A
authors.lastname: Pugliese
authors.forename: Jishuai
authors.initials: J
authors.lastname: Zhang
authors.forename: Ann M
authors.initials: AM
authors.lastname: Bode
authors.forename: Ziming
authors.initials: Z
authors.lastname: Dong
authors.forename: Zigang
authors.initials: Z
authors.lastname: Dong
mesh_terms: D051697:Activating Transcription Factor 1 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism*; D004815:Epidermal Growth Factor / Q000378:metabolism / Q000494:pharmacology*; D044950:Flavanones / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D017434:Protein Structure, Tertiary; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D015533:Transcriptional Activation / Q000187:drug effects; D018631:ras Proteins
chemical_list: D051697:Activating Transcription Factor 1; C497100:Atf1 protein, mouse; D044950:Flavanones; D004815:Epidermal Growth Factor; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C069330:ribosomal protein S6 kinase, 90kDa, polypeptide 3; D020929:Mitogen-Activated Protein Kinase Kinases; D018631:ras Proteins; C007619:eriodictyol