Conformational changes in a transcription factor can significantly affect its transcriptional activity. The activated form of the FOXM1 transcription factor regulates the transcriptional network of genes essential for cell cycle progression and carcinogenesis. However, the mechanism and impact of FOXM1 conformational change on its transcriptional activity in vivo throughout the cell cycle progression remain unexplored. Here, we demonstrate that FOXM1 proteins form novel intermolecular homodimerizations in vivo, and these conformational changes in FOXM1 homodimers impact activity during the cell cycle. Specifically, during the G1 phase, FOXM1 undergoes autorepressive homodimerization, wherein the αβα motif in the C-terminal transcriptional activation domain interacts with the ββαβ motif in the N-terminal repression domain, as evidenced by FRET imaging. Phosphorylation of the αβα motif by PLK1 at S715/S724 disrupts ββαβ–αβα hydrophobic interactions, thereby facilitating a conserved αβα motif switch binding partner to the novel intrinsically disordered regions, leading to FOXM1 autostimulatory homodimerization persisting from the S phase to the G2/M phase in vivo. Furthermore, we identified a minimal ββαβ motif peptide that effectively inhibits cancer cell proliferation both in cell culture and in a mouse tumor model, suggesting a promising autorepression approach for targeting FOXM1 in cancer therapy.

中文翻译：

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FOXM1 同型二聚体在体内的构象对于调节转录活性至关重要


转录因子的构象变化会显著影响其转录活性。FOXM1 转录因子的激活形式调节细胞周期进程和致癌作用所必需的基因转录网络。然而，FOXM1 构象变化在整个细胞周期进程中对其体内转录活性的机制和影响仍未得到探索。在这里，我们证明 FOXM1 蛋白在体内形成新的分子间同源二聚化，并且 FOXM1 同源二聚体的这些构象变化会影响细胞周期中的活性。具体来说，在 G1 期，FOXM1 经历自抑制性同源二聚化，其中 C 端转录激活结构域中的 αβα 基序与 N 端抑制结构域中的 ββαβ 基序相互作用，FRET成像证明了这一点。PLK1 在 S715/S724 位点对 αβα 基序的磷酸化破坏了 ββαβ-αβα 疏水相互作用，从而促进了保守的 αβα 基序开关结合伴侣到新的内在无序区域，导致 FOXM1 自刺激同源二聚化在体内从 S 期持续到 G2/M 期。此外，我们鉴定了一种最小的 ββαβ 基序肽，可在细胞培养和小鼠肿瘤模型中有效抑制癌细胞增殖，表明在癌症治疗中靶向 FOXM1 是一种有前途的自抑制方法。