The Smad7-Skp2 complex orchestrates Myc stability, impacting on the cytostatic effect of TGF-β

• Published in: Journal of cell science Vol. 127; no. Pt 2; pp. 411 - 421
• Main Authors: Kim, Tae-Aug, Kang, Jin Muk, Hyun, Ja-Shil, Lee, Bona, Kim, Staci Jakyong, Yang, Eun-Sung, Hong, Suntaek, Lee, Ho-Jae, Fujii, Makiko, Niederhuber, John E, Kim, Seong-Jin
• Format: Journal Article
• Language: English
• Published: England The Company of Biologists 15.01.2014
• Subjects: Cell Line, Tumor; Cytostatic Agents - pharmacology; Down-Regulation - drug effects; Gene Expression Regulation, Neoplastic - drug effects; HEK293 Cells; Humans; Inhibitor of Differentiation Proteins - genetics; Inhibitor of Differentiation Proteins - metabolism; Proteasome Endopeptidase Complex - metabolism; Protein Binding - drug effects; Protein Interaction Domains and Motifs; Protein Interaction Mapping; Protein Stability - drug effects; Proteolysis - drug effects; Proto-Oncogene Proteins c-myc - metabolism; S-Phase Kinase-Associated Proteins - metabolism; Smad7 Protein - metabolism; Transcription, Genetic - drug effects; Transforming Growth Factor beta - pharmacology; Ubiquitin - metabolism; Protein stability; Skp2; Myc; Ubiquitylation; Smad7
• ISSN: 0021-9533; 1477-9137
• DOI: 10.1242/jcs.136028

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.