| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2004: ¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 2003: ¥1,800,000 (Direct Cost: ¥1,800,000)
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| Research Abstract |
Members of the transforming growth factor-β (TGF-β) superfamily, including TGF-β, activin, nodal, and bone morphogenetic proteins (BMPs), are multifunctional cytokines that regulate a wide range of cellular responses, including cell proliferation, differentiation, adhesion, migration, and apoptosis. TGF-β and related proteins transduce signals through two distinct serine/threonine kinase receptors, termed type I and type II, and intracellular Smad proteins. Eight different Smad proteins have been identified in mammals, and are classified into three groups : receptor-regulated Smads (R-Smads), common-partner Smad (Co-Smad), and inhibitory Smads (I-Smads). Smad2 and Smad3 are R-Smads activated by TGF-β/activin/nodal receptors ALK-4, -5, and -7, whereas Smad1, Smad5, and Smad8 are BMP-specific R-Smads. Smad4 is the Co-Smad shared by signaling pathways for TGF-β and activin and those for BMPs. Smad6 and Smad7 are I-Smads in mammals ; Smad6 preferentially suppresses BMP signaling, whereas S
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mad7 inhibits both BMP and TGF-β signaling.
The roles of TGF-β in cancer biology are complex ; TGF-β can suppress or promote tumor growth depending on the type of cancer. The ability of TGF-β to potently inhibit the proliferation of epithelial, endothelial, and hematopoietic cell lineages is central to its tumor-suppressive effects. However, as tumors evolve, they often become refractory to TGF-β-mediated growth inhibition and overexpress TGF-β, which induces epithelial-to-mesenchymal transition (EMT) of tumor cells and facilitates immunosuppression, extracellular matrix deposition, and angiogenesis. It was recently reported that inhibition of autocrine TGF-β signaling in carcinoma cells reduces cell invasiveness and tumor metastasis, and that these effects of TGF-β are closely associated with the ability of TGF-β to induce EMT and stimulate cell migration. The TGF-β signaling pathway has correspondingly become an attractive target for drug development in the field of oncology.
To identify new components of transcriptional complexes containing Smad proteins, we purified DNA-binding proteins from human breast cancer MCF-7 cell nuclear extract using a Smad-binding DNA element as bait, and identified a co-activator GCN5 as a direct partner of activated Smad complexes. GCN5 is structurally similar to PCAF, which was previously identified as a co-activator for R-Smads for TGF-β signaling pathways. GCN5 functions like PCAF, in that it binds to TGF-β-specific R-Smads, and enhances transcriptional activity induced by TGF-β. In addition, GCN5, but not PCAF, interacts with R-Smads for BMP signaling pathways, and enhances BMP-induced transcriptional activity, suggesting that GCN5 and PCAF have distinct physiological functions in vivo. Moreover, silencing of the GCN5 gene by RNA interference results in repression of transcriptional activities induced by TGF-β. Less
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