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SMAD4, a key regulator of transforming growth factor-β (TGF-β) signaling, plays a major role in cell growth, migration, and apoptosis. In particular, TGF-β/SMAD induces growth arrest, and SMAD4 induces the expression of target genes such as <i>p21WAF1</i> and <i>p15INK4b</i> through its interaction with several cofactors. Thus, inactivating mutations or the homozygous deletion of <i>SMAD4</i> could be related to tumorigenesis or malignancy progression. However, in some cancer types, <i>SMAD4</i> is neither mutated nor deleted. In the current study, we demonstrate that TGF-β signaling with a preserved SMAD4 function can contribute to cancer through associations with negative pathway regulators. We found that nuclear respiratory factor-1 (NRF1) is a novel interaction SMAD4 partner that inhibits TGF-β/SMAD4-induced <i>p15INK4b</i> mRNA expression by binding to SMAD4. Furthermore, we confirmed that NRF1 directly binds to the core region of the <i>SMAD4</i> promoter, thereby decreasing <i>SMAD4</i> mRNA expression. On the whole, our data suggest that NRF1 is a negative regulator of SMAD4 and can interfere with TGF-β/SMAD-induced tumor suppression. Our findings provide a novel perception into the molecular basis of TGF-β/SMAD4-signaling suppression in tumorigenesis.