title: The Smad7-Skp2 complex orchestrates Myc stability, impacting on the cytostatic effect of TGF-β.
abstract: In most human cancers the Myc proto-oncogene is highly activated. Dysregulation of Myc oncoprotein contributes to tumorigenesis in numerous tissues and organs. Thus, targeting Myc stability could be a crucial step for cancer therapy. Here we report Smad7 as a key molecule regulating Myc stability and activity by recruiting the F-box protein, Skp2. Ectopic expression of Smad7 downregulated the protein level of Myc without affecting the transcription level, and significantly repressed its transcriptional activity, leading to inhibition of cell proliferation and tumorigenic activity. Furthermore, Smad7 enhanced ubiquitylation of Myc through direct interaction with Myc and recruitment of Skp2. Ablation of Smad7 resulted in less sensitivity to the growth inhibitory effect of TGF-β by inducing stable Myc expression. In conclusion, these findings that Smad7 functions in Myc oncoprotein degradation and enhances the cytostatic effect of TGF-β signaling provide a possible new therapeutic approach for cancer treatment.
authors.affiliation: CHA Cancer Institute, CHA University, Seoul 135-081, Korea.
authors.forename: Tae-Aug
authors.initials: TA
authors.lastname: Kim
authors.forename: Jin Muk
authors.initials: JM
authors.lastname: Kang
authors.forename: Ja-Shil
authors.initials: JS
authors.lastname: Hyun
authors.forename: Bona
authors.initials: B
authors.lastname: Lee
authors.forename: Staci Jakyong
authors.initials: SJ
authors.lastname: Kim
authors.forename: Eun-Sung
authors.initials: ES
authors.lastname: Yang
authors.forename: Suntaek
authors.initials: S
authors.lastname: Hong
authors.forename: Ho-Jae
authors.initials: HJ
authors.lastname: Lee
authors.forename: Makiko
authors.initials: M
authors.lastname: Fujii
authors.forename: John E
authors.initials: JE
authors.lastname: Niederhuber
authors.forename: Seong-Jin
authors.initials: SJ
authors.lastname: Kim
mesh_terms: D045744:Cell Line, Tumor; D054697:Cytostatic Agents / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D051796:Inhibitor of Differentiation Proteins / Q000235:genetics / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D054730:Protein Interaction Domains and Motifs; D025941:Protein Interaction Mapping; D055550:Protein Stability / Q000187:drug effects; D059748:Proteolysis / Q000187:drug effects; D000090063:Proto-Oncogene Mas; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D044786:S-Phase Kinase-Associated Proteins / Q000378:metabolism*; D051906:Smad7 Protein / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D054697:Cytostatic Agents; D051796:Inhibitor of Differentiation Proteins; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D016271:Proto-Oncogene Proteins c-myc; D044786:S-Phase Kinase-Associated Proteins; C497806:SMAD7 protein, human; D051906:Smad7 Protein; D016212:Transforming Growth Factor beta; D025801:Ubiquitin; D046988:Proteasome Endopeptidase Complex
keywords: Myc; Protein stability; Skp2; Smad7; Ubiquitylation