Laboratory of Molecular Pathology and Cancer Genomics, Research Institute of Pharmaceutical Sciences and College of Pharmacy, Seoul National University, Seoul 08826, Korea.
College of Pharmacy, Duksung Women's University, Seoul 01369, Korea.
Int J Mol Sci. 2021 May 25;22(11):5595. doi: 10.3390/ijms22115595.
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 and through its interaction with several cofactors. Thus, inactivating mutations or the homozygous deletion of could be related to tumorigenesis or malignancy progression. However, in some cancer types, 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 mRNA expression by binding to SMAD4. Furthermore, we confirmed that NRF1 directly binds to the core region of the promoter, thereby decreasing 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.
SMAD4 是转化生长因子-β（TGF-β）信号的关键调节因子，在细胞生长、迁移和凋亡中发挥重要作用。特别是，TGF-β/SMAD 诱导生长停滞，SMAD4 通过与几个共因子相互作用诱导 和 等靶基因的表达。因此， 的失活突变或纯合缺失可能与肿瘤发生或恶性进展有关。然而，在某些癌症类型中， 既没有突变也没有缺失。在本研究中，我们证明具有保留 SMAD4 功能的 TGF-β 信号可以通过与负途径调节剂的关联促进癌症。我们发现核呼吸因子-1（NRF1）是一种新型的 SMAD4 相互作用伙伴，通过与 SMAD4 结合抑制 TGF-β/SMAD4 诱导的 mRNA 表达。此外，我们证实 NRF1 直接结合到 启动子的核心区域，从而降低 mRNA 表达。总的来说，我们的数据表明 NRF1 是 SMAD4 的负调节剂，可以干扰 TGF-β/SMAD 诱导的肿瘤抑制。我们的研究结果为 TGF-β/SMAD4 信号抑制在肿瘤发生中的分子基础提供了新的认识。
