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未得到探索。在这里，我们展示了 MNT 和 REL（NF-κB 家族的致癌成员）之间的一种新的 MAX 独立蛋白相互作用。REL 参与重要的生物学过程，并在多种肿瘤中发生改变。REL 是一种转录因子，它在细胞质中与 IκB 形成抑制复合物，在 NF-κB 通路被激活时易位至细胞核。MNT敲低触发 REL 易位进入细胞核，从而激活 NF-κB 通路。同时，MNT过表达会抑制真正的 REL 靶标 IκBα。MNT 和 REL 都与第一个外显子上的 IκBα 基因结合，表明其作为 MNT-REL 复合物进行调节。总之，我们的数据表明 MNT 通过两种机制充当 NF-κB 通路的阻遏物：(1) 通过 MNT 相互作用将 REL 保留在细胞质中，以及 (2) MNT 驱动的 REL 靶基因抑制通过 MNT– REL 复杂。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 通路之间的新联系，这两个通路是癌症中最重要的通路。