Smad7 mediates apoptosis induced by transforming growth factor beta in prostatic carcinoma cells.
Transforming growth factor beta (TGF-beta) is an important regulator of apoptosis in some cell types, but the underlying molecular mechanisms are largely unknown. TGF-beta signals through type I and type II receptors and downstream effector proteins, termed Smads. TGF-beta induces the phosphorylation of Smad2 and Smad3 (receptor-activated Smads) which associate with Smad4 and translocate to the nucleus, where they regulate gene transcription [1]. Smad7 protein is induced by TGF-beta1 and has been classified as an inhibitory Smad. Smad7 prevents phosphorylation of receptor-activated Smads, thereby inhibiting TGF-beta-induced signaling responses [1]. Smad7 expression is increased in rat prostatic epithelial cells undergoing apoptosis as a result of castration [2]. Here we have shown that TGF-beta1 treatment or ectopic expression of Smad7 in human prostatic carcinoma cells (PC-3U) induces apoptosis. Furthermore, TGF-beta1-induced apoptosis was prevented by inhibition of Smad7 expression, by antisense mRNA in stably transfected cell lines or upon transient transfection with antisense oligonucleotides in several investigated cell lines. These findings provide evidence for a new effector function for Smad7 in TGF-beta1 signaling.
Landström
M
M
Biomedical Centre, Rudbeck Laboratory, Ludwig Institute for Cancer Research, Uppsala University, Uppsala, Sweden. Marene.Landstrom@LICR. uu.se
Heldin
N E
NE
Bu
S
S
Hermansson
A
A
Itoh
S
S
ten Dijke
P
P
Heldin
C H
CH
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D017209:Apoptosis; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms; D015398:Signal Transduction; D051906:Smad7 Protein; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism* / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D000590:Amino Acid Chloromethyl Ketones; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D004268:DNA-Binding Proteins; C497806:SMAD7 protein, human; D051906:Smad7 Protein; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone