01.教師研究專案_王翊青
生物科技研究所 王翊青副教授
Institute of Biotechnology, Associate Professor I-Ching Wang
教師(作者團隊)相片Faculty (Author Team) Photo照片 |
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Paper Title |
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The conformation of FOXM1 homodimers in vivo is crucial for regulating transcriptional activities. |
The conformation of FOXM1 homodimers in vivo is crucial for regulating transcriptional activities. |
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核酸研究 Nucleic Acids Research |
Nucleic Acids Research |
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Research Team |
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主持人： 王翊青 副教授 國立清華大學生命科學暨醫學院 生物科技研究所
參與者： 許嘉展 博士 國立清華大學生命科學暨醫學院 生物科技研究所 姚翔 國立清華大學生命科學暨醫學院 生物科技研究所 陳尚耀 國立清華大學生命科學暨醫學院 生物科技研究所 鄒粹軍 研究員 國家衛生研究院 國家環境衛生科學研究所 |
Principle Investigator: I-Ching Wang, Associate Professor Institute of Biotechnology (IBT), College of Life Science and Medicine (CLSM), National Tsing Hua University (NTHU).
Participants: Chia-Chan Hsu, Ph.D. IBT, CLSM, NTHU
Xiang Yao. IBT, CLSM, NTHU
Shang-Yao Chen IBT, CLSM, NTHU
Tsui-Chun Tsuo, Ph.D. Investigator, National Institute of Environmental Health Sciences, National Health and Research Institutes (NHRI) |
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研究成果 |
Result/Contributions |
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FOXM1轉錄因子在癌細胞中的表現量顯著上升，且活性異常增加，被認為是多種癌症惡化的重要驅動因子。臨床研究顯示，FOXM1不僅可做為癌症病人預後的生物標誌，亦是一個極具潛力的精準治療標靶。 本研究首度發現， FOXM1蛋白在活體中以「二聚體」(dimer)的形式存在，而二聚體構型會隨細胞週期進程而轉換。當細胞週期進入G1期，FOXM1蛋白透過C端αβα結構域與N端的ββαβ結構域相互作用，形成「自抑制」的二聚體構型。隨著細胞週期進入S期，PLK1激脢對FOXM1的S715和S724位點進行磷酸化修飾，誘導蛋白構型發生變化，此時，C端αβα結構域與內在無結構區段（IDR）結合，使FOXM1從而轉換成「自活化」二聚體構型，進而提升其轉錄活性並調控細胞分裂相關基因表現。基於此發現，我們進一步找出調控FOXM1蛋白構型轉換的關鍵短胜肽序列，並透過表現該短胜肽成功地干擾FOXM1活性，並顯著地抑制體外培養肺腺癌細胞增生，在小鼠腫瘤模型也展現顯著的抑制腫瘤效果。本研究證明，透過精準干預FOXM1蛋白活性，將有望開展癌症治療的新策略。 本論文研究包含分子機制研究及小鼠腫瘤模式實驗，歷時近8年，共建構出近200個DNA質體進行多種測試。本論文的相關內容曾於2023美國癌症協會(AACR)年會上進行海報展示，並於2024年12月發表於國際頂尖期刊Nucleic Acids Research (impact factor 16.7)。 |
The expression level of the transcription factor FOXM1 is significantly elevated in cancer cells, with abnormally increased activity, and is considered a major driver of progression in various cancers. Clinical studies have shown that FOXM1 can serve not only as a biomarker for cancer prognosis but also as a highly promising target for precision therapy. This study is the first to discover that FOXM1 protein exists in vivo as a homodimer, and that its dimeric conformation changes along with cell cycle progression. In the G1 phase, FOXM1 forms a self-inhibited dimeric configuration through interactions between the C-terminal αβα domain and the N-terminal ββαβ domain. As the cell progresses into the S phase, the kinase PLK1 phosphorylates FOXM1 at residues S715 and S724, triggering a conformational change. At this point, the C-terminal αβα domain interacts with an intrinsically disordered region (IDR), transforming FOXM1 into a self-activated dimeric form, thereby enhancing its transcriptional activity and regulating the expression of cell division-related genes. Based on this discovery, we identified a key short peptide sequence that modulates FOXM1’s conformational switch. By expressing this peptide, we successfully interfered with FOXM1 activity, significantly inhibiting the proliferation of cultured lung adenocarcinoma cells, and demonstrated potent anti-tumor effects in a mouse tumor model. This study proves that precise inhibition of FOXM1 activity may offer a novel strategy for cancer treatment. The research included both molecular mechanism studies and mouse tumor model experiments and spanned nearly eight years, during which nearly 200 DNA plasmids were constructed for various tests. Related findings from this study were presented as a poster at the 2023 American Association for Cancer Research (AACR) Annual Meeting, and the full study was published in December 2024 in the top-tier international journal Nucleic Acids Research (impact factor 16.7). |
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Related Information |
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中華日報 |
China Daily News |
