Transcriptional induction of Smurf2 ubiquitin ligase by TGF-beta.
Smad ubiquitination regulatory factor 2 (Smurf2), a ubiquitin ligase for Smads, plays critical roles in the regulation of transforming growth factor-beta (TGF-beta)-Smad signaling via ubiquitin-dependent degradation of Smad2 and Smad7. We found that TGF-beta stimulates Smurf2 expression. TGF-beta activated the Smurf2 promoter in a TGF-beta responsive cell lines, whereas IL-1alpha, PDGF and epidermal growth factor did not. TGF-beta-mediated Smurf2 promoter activation was inhibited by Smad7 or an activin receptor-like kinase 5 inhibitor but not by dominant negative Smad or disruption of Smad-binding elements in the promoter. Moreover, inhibition of the phosphatidil inositol 3 kinase (PI3K)/Akt pathway suppressed TGF-beta-mediated Smurf2 induction. These results suggest that TGF-beta stimulates Smurf2 expression by Smad-independent pathway such as PI3K/Akt pathway via TGF-beta receptor.
Ohashi
Naro
N
First Department of Medicine, Hamamatsu University School of Medicine, Shizuoka, Japan. ohashi-n@hama.med.ac.jp
Yamamoto
Tatsuo
T
Uchida
Chiharu
C
Togawa
Akashi
A
Fukasawa
Hirotaka
H
Fujigaki
Yoshihide
Y
Suzuki
Sayuri
S
Kitagawa
Kyoko
K
Hattori
Takayuki
T
Oda
Toshiaki
T
Hayashi
Hidetoshi
H
Hishida
Akira
A
Kitagawa
Masatoshi
M
D015153:Blotting, Western; D045744:Cell Line, Tumor; D024202:Electrophoretic Mobility Shift Assay; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D006367:HeLa Cells; D006801:Humans; D008025:Ligases / Q000096:biosynthesis*; D008156:Luciferases / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D025801:Ubiquitin / Q000096:biosynthesis*; D044767:Ubiquitin-Protein Ligases / Q000096:biosynthesis*
D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D025801:Ubiquitin; D008156:Luciferases; C471641:SMURF2 protein, human; D044767:Ubiquitin-Protein Ligases; D008025:Ligases