MNT, a transcription factor of the MXD family, is an important modulator of the oncoprotein MYC. Both MNT and MYC are basic-helix–loop–helix proteins that heterodimerize with MAX in a mutually exclusive manner, and bind to E-boxes within regulatory regions of their target genes. While MYC generally activates transcription, MNT represses it. However, the molecular interactions involving MNT as a transcriptional regulator beyond the binding to MAX remain unexplored. Here we demonstrate a novel MAX-independent protein interaction between MNT and REL, the oncogenic member of the NF-κB family. REL participates in important biological processes and it is altered in a variety of tumors. REL is a transcription factor that remains inactive in the cytoplasm in an inhibitory complex with IκB and translocates to the nucleus when the NF-κB pathway is activated. In the present manuscript, we show that MNT knockdown triggers REL translocation into the nucleus and thus the activation of the NF-κB pathway. Meanwhile, MNT overexpression results in the repression of IκBα, a bona fide REL target. Both MNT and REL bind to the IκBα gene on the first exon, suggesting its regulation as an MNT–REL complex. Altogether our data indicate that MNT acts as a repressor of the NF-κB pathway by two mechanisms: (1) retention of REL in the cytoplasm by MNT interaction, and (2) MNT-driven repression of REL-target genes through an MNT–REL complex. These results widen our knowledge about MNT biological roles and reveal a novel connection between the MYC/MXD and NF-κB pathways, two of the most prominent pathways in cancer.

MNT 是 MXD 家族的转录因子，是癌蛋白 MYC 的重要调节剂。 MNT 和 MYC 都是碱性螺旋-环-螺旋蛋白，它们以互斥的方式与 MAX 异二聚化，并与其靶基因调控区域内的 E-box 结合。虽然 MYC 通常会激活转录，但 MNT 会抑制它。然而，除了与 MAX 结合之外，涉及 MNT 作为转录调节因子的分子相互作用仍有待探索。在这里，我们展示了 MNT 和 REL（NF-κB 家族的致癌成员）之间一种新型的不依赖于 MAX 的蛋白质相互作用。 REL 参与重要的生物过程，并且在多种肿瘤中发生改变。 REL 是一种转录因子，在细胞质中与 IκB 形成抑制复合物，保持失活状态，并在 NF-κB 通路激活时转位至细胞核。在本手稿中，我们表明MNT敲低会触发 REL 易位到细胞核中，从而激活 NF-κB 通路。同时， MNT过度表达会抑制真正的 REL 靶标 IκBα。 MNT 和 REL 均与第一个外显子上的 IκBα 基因结合，表明其作为 MNT-REL 复合体进行调节。总而言之，我们的数据表明，MNT 通过两种机制发挥 NF-κB 通路抑制因子的作用：（1）通过 MNT 相互作用将 REL 保留在细胞质中，以及（2）MNT 通过 MNT 驱动的 REL 靶基因抑制REL 复合体。这些结果拓宽了我们对 MNT 生物学作用的认识，并揭示了 MYC/MXD 和 NF-κB 通路（癌症中两个最重要的通路）之间的新联系。