Transforming growth factor-beta suppresses the ability of Ski to inhibit tumor metastasis by inducing its degradation.
c-Ski is an important corepressor of transforming growth factor-beta (TGF-beta) signaling through its ability to bind to and repress the activity of the Smad proteins. It was initially identified as an oncogene that promotes anchorage-independent growth of chicken and quail embryo fibroblasts when overexpressed. Although increased Ski expression is detected in many human cancer cells, the roles of Ski in mammalian carcinogenesis have yet to be defined. Here, we report that reducing Ski expression in breast and lung cancer cells does not affect tumor growth but enhances tumor metastasis in vivo. Thus, in these cells, Ski plays an antitumorigenic role. We also showed that TGF-beta, a cytokine that is often highly expressed in metastatic tumors, induces Ski degradation through the ubiquitin-dependent proteasome in malignant human cancer cells. On TGF-beta treatment, the E3 ubiquitin ligase Arkadia mediates degradation of Ski in a Smad-dependent manner. Although Arkadia interacts with Ski in the absence of TGF-beta, binding of phosphorylated Smad2 or Smad3 to Ski is required to induce efficient degradation of Ski by Arkadia. Our results suggest that the ability of TGF-beta to induce degradation of Ski could be an additional mechanism contributing to its protumorigenic activity.
Le Scolan
Erwan
E
Department of Molecular and Cell Biology, University of California Berkeley, Berkeley, CA 94720, USA.
Zhu
Qingwei
Q
Wang
Long
L
Bandyopadhyay
Abhik
A
Javelaud
Delphine
D
Mauviel
Alain
A
Sun
LuZhe
L
Luo
Kunxin
K
D000818:Animals; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism* / Q000502:physiology; D005260:Female; D016147:Genes, Tumor Suppressor / Q000187:drug effects; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009362:Neoplasm Metastasis / Q000473:pathology*; D009687:Nuclear Proteins / Q000502:physiology; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism* / Q000502:physiology; D051785:Smad Proteins / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D044767:Ubiquitin-Protein Ligases
D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; C060614:SKI protein, human; C486067:RNF111 protein, human; D044767:Ubiquitin-Protein Ligases