轉錄因子的蛋白構型變化對其轉錄活性具有顯著影響。已知活化態的FOXM1轉錄因子能調控基因轉錄網絡，從而驅動細胞週期進程，這與癌症發展至關重要。然而，在細胞週期進程中，FOXM1的蛋白構型變化、其分子機制及其對轉錄活性的影響仍未完成明瞭。在本論文中，我們發現FOXM1蛋白在活細胞內以一種前所未見的分子間同源二聚體構型存在，且構型於細胞週期中會因變化而影響其轉錄活性。具體而言，透過螢光共振能量轉移(FRET)成像實驗，我們證明在G1期時，FOXM1的羧基(C)端轉錄活化域(TAD)中的αβα模體與其位於胺基(N)端抑制域(NRD)中的ββαβ模體相互作用，形成自我抑制的同源二聚化構型。隨著細胞週期進入S期到G2/M期，PLK1對αβα模體S715/S724位點進行磷酸化，進而改變αβα-ββαβ間的疏水性相互作用，從而促使αβα模體結構轉變而與新發現的內在無序區域(IDRs)發生結合，促使FOXM1形成一種自活化的同源二聚體，並持續存在到細胞質分裂。此外，我們分析出一段具生物功能的最小ββαβ模體序列，可在細胞培養實驗和小鼠腫瘤模型中有效抑制癌細胞增殖。透過了解此些FOXM1自我抑制機制，我們期望為開發出針對FOXM1的癌症治療新策略奠定基礎。

Conformational changes in a transcription factor can significantly alter its transcriptional activity in distinct ways. The activated form of the FOXM1 transcription factor regulates a complex network of gene expression essential for cell cycle progression and carcinogenesis. However, the mechanism regarding transcriptional activation of FOXM1 in response to conformational changes in vivo throughout the cell cycle progression remain unexplored. Here, we demonstrate that FOXM1 proteins form previously unreported 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 (TAD) interacts with the ββαβ motif in the N-terminal repression domain (NRD), as shown by FRET imaging. Phosphorylation of the αβα motif by PLK1 at S715/S724 weakens ββαβ-αβα hydrophobic interactions, thereby facilitating a conserved αβα motif switch binding partner to the novel intrinsically disordered regions (IDRs), 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 restricts cancer cell proliferation both in cell culture and in a mouse tumor model, suggesting a promising autorepression approach for targeting FOXM1 in cancer therapy.

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