Trends in Molecular Medicine
Research updateSmad7: a new key player in TGF-β-associated disease
Section snippets
Smad7 is a major inhibitory regulator for TGF-β/Smad signaling
The identification of Smad proteins has advanced our understanding of how TGF-β signals from the membrane to the nucleus [4]. The activated TGF-β receptors phosphorylate Smad2 and Smad3, which form heteromeric complex with Smad4 and enter the nucleus, bind to DNA in a sequence-specific manner, and regulate gene transcription in cooperation with various transcriptional factors and coactivators and/or corepressors.
Recent studies have identified several molecules that control the signal
Aberrant expression of Smad7 impairs efficient TGF-β signaling in IBD and scleroderma
Recent studies have implicated Smad7 as an important molecule for regulating TGF-β activity in human disease (Fig. 2). Monteleone et al. reported that Smad7 was overexpressed in IBD mucosa and purified mucosal T cells [2]. Both whole tissue and isolated cells exhibited defective TGF-β signaling as measured by phospho-Smad3 immunoreactivity. Importantly, antisense oligonucleotides for Smad7 restored TGF-β signaling and enabled TGF-β to inhibit pro-inflammatory cytokine production such as
Perspectives
Many in vitro and in vivo animal studies have implicated Smad7 as a major inhibitory regulator of the TGF-β–Smad pathway. It is well known that signal-transduction pathways have their own intracellular regulators and there is much cross-talk signaling regulation through regulatory molecules such as Smad7 [4]. This regulatory role for Smad7 is supported by the findings in the IBD and scleroderma studies in humans 2., 3..
Upregulation of TGF-β has been documented in certain inflammatory disorders
Acknowledgements
We thank Hiroko Ushio, Keiko Maeda, Chiharu Nishiyama, Toshiro Takai, Yutaka Kanamaru, Koji Sumiyoshi, Toshinari Funaki, Nobuyuki Ebihara, Yasuhiro Setoguchi, and Ryoji Tsuboi for helpful discussion and support. This work was supported in part by a grant from the Ministry of Education, Culture, Sports, Science, and Technology, Japan.
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