Arkadia regulates TGF-beta signaling during renal tubular epithelial to mesenchymal cell transition.
Transforming growth factor-beta (TGF-beta) signaling has been linked with tubular epithelial to mesenchymal cell transition. In this study, we examined the role of Arkadia, an E3 ubiquitin ligase that is critically required for TGF-beta signaling during epithelial to mesenchymal cell transition. We found that when normal human renal tubular epithelial cells in culture were stimulated with TGF-beta1, which increased their levels of Arkadia, Smurf2, TGF-beta type I receptor (TbetaRI), and Smad7 mRNA, but had low levels of Smad7 protein. When these cells were preincubated with Arkadia siRNA (small interfering RNA) and lactacystin (an inhibitor of proteasomal degradation), the TGF-beta(1) induced expression of Smad7, alpha-smooth muscle actin, and E-cadherin was partly reversed, but the expression of TbetaRI protein and Smad7 mRNA was not affected. In contrast, Smurf2 siRNA had no influence on the expression of these targets. Our studies suggest that Arkadia stimulates renal tubular epithelial to mesenchymal cell transition through degradation of Smad7.
Department of Nephrology, the Second Xiangya Hospital of Central South University, Changsha, Hunan, China. xiaozhaosun@hotmail.com
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D000199:Actins / Q000235:genetics / Q000378:metabolism; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D004848:Epithelium / Q000201:enzymology / Q000473:pathology; D005355:Fibrosis; D006801:Humans; D007674:Kidney Diseases / Q000201:enzymology / Q000473:pathology*; D007684:Kidney Tubules / Q000187:drug effects / Q000201:enzymology / Q000473:pathology*; D008648:Mesoderm / Q000201:enzymology / Q000473:pathology*; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014176:Protein Biosynthesis / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051906:Smad7 Protein / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism / Q000494:pharmacology; D044767:Ubiquitin-Protein Ligases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
C541116:ACTA2 protein, human; D000199:Actins; D015820:Cadherins; D009687:Nuclear Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D018125:Receptors, Transforming Growth Factor beta; D051906:Smad7 Protein; D016212:Transforming Growth Factor beta; C471641:SMURF2 protein, human; C486067:RNF111 protein, human; D044767:Ubiquitin-Protein Ligases; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I