Context-dependent regulation of the expression of c-Ski protein by Arkadia in human cancer cells.
Arkadia is a positive regulator of transforming growth factor-beta (TGF-beta) signalling, which induces ubiquitylation and proteasome-dependent degradation of negative regulators of the TGF-beta signalling pathway, i.e. Smad7, c-Ski and SnoN. In the present study, we examined the roles of Arkadia in human cancer cells. We first examined the expression of Arkadia in 20 cancer cell lines and 2 non-cancerous cell lines, and found that it was expressed ubiquitously at both the mRNA and protein levels. Interestingly, levels of expression of c-Ski protein, one of the substrates of Arkadia, were not correlated with those of c-Ski mRNA. Arkadia induced down-regulation of c-Ski protein expression in many cell lines examined, but did not in certain cell lines with high levels of expression of c-Ski protein. We also found that knockdown of Arkadia attenuated the induction of TGF-beta target genes, whereas ectopically expressed Arkadia enhanced it. Notably, over-expression of Arkadia inhibited the growth of HepG2 cells in the presence as well as the absence of TGF-beta stimulation. Arkadia thus regulates the levels of expression of c-Ski protein in cell-type-dependent fashion, and exhibits a tumour suppressor function by inhibiting tumour cell growth.
Nagano
Yoshiko
Y
Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo, Japan.
Koinuma
Daizo
D
Miyazawa
Keiji
K
Miyazono
Kohei
K
D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering; D015398:Signal Transduction; D013997:Time Factors; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*
D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C060615:SKIL protein, human; C512653:Ski protein, mouse; D053773:Transforming Growth Factor beta1; C060614:SKI protein, human; C486067:RNF111 protein, human; C427283:Rnf111 protein, mouse; D044767:Ubiquitin-Protein Ligases