Induction of inhibitory Smad6 and Smad7 mRNA by TGF-beta family members.
Smad6 and Smad7 function as intracellular antagonists in transforming growth factor-beta (TGF-beta) signaling. Here we report the isolation of human Smad6, which is closely related to Smad7. Smad6 and Smad7 mRNAs were differentially expressed in lung cancer cell lines and were rapidly and directly induced by TGF-beta1, activin and bone morphogenetic protein-7. Cross-talk between TGF-beta and other signaling pathways was demonstrated by the finding that epidermal growth factor (EGF) induced the expression of inhibitory SMAD mRNA. Moreover, whereas the phorbol ester PMA alone had no effect, it potentiated the TGF-beta1-induced expression of Smad7 mRNA. Ectopic expression of anti-sense Smad7 RNA was found to increase the effect of TGF-beta1, supporting its role as a negative regulator in TGF-beta signaling. Thus, expression of inhibitory Smads is induced by multiple stimuli, including the various TGF-beta family members, whose action they antagonize.
Unit of Pathology, University Hospital, Uppsala, S-751 85, Sweden. Mozhgan.Afrakhte@patologi.uu.se
M
M
Afrakhte
A
A
Morén
S
S
Jossan
S
S
Itoh
K
K
Sampath
B
B
Westermark
C H
CH
Heldin
N E
NE
Heldin
P
P
ten Dijke
D028341:Activins; D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000494:pharmacology; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics*; D004357:Drug Synergism; D004815:Epidermal Growth Factor / Q000494:pharmacology; D004847:Epithelial Cells; D015870:Gene Expression; D006801:Humans; D007265:Inhibins / Q000494:pharmacology; D015603:Keratinocytes; D008168:Lung; D008175:Lung Neoplasms / Q000378:metabolism; D008907:Mink; D012333:RNA, Messenger / Q000096:biosynthesis*; D015398:Signal Transduction; D051905:Smad6 Protein; D051906:Smad7 Protein; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D015534:Trans-Activators; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D019485:Bone Morphogenetic Proteins; D004268:DNA-Binding Proteins; D012333:RNA, Messenger; C497802:SMAD6 protein, human; C497806:SMAD7 protein, human; D051905:Smad6 Protein; D051906:Smad7 Protein; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D028341:Activins; D007265:Inhibins; D004815:Epidermal Growth Factor; D013755:Tetradecanoylphorbol Acetate