细胞周期调控因子FOXM1的乙酰化促进MnSOD转录抑制细胞衰老的分子机制研究

Cell cycle arrest is a typical feature of cellular senescence.The transcription factor FOXM1 is essential for cell cycle regulation.It is reported that FOXM1 can inhibit cell senescence, but the mechanism is still unclear. Our previous studies indicated that FOXM1 can be acetylated by p300/CBP. FOXM1 acetylation can promote tumor cell proliferation and tumor growth, but its role in cellular senescence is not well defined. Our previous studies has manifested that FOXM1 acetylation levels increased significantly under oxidative stress; acetylation-deficient FOXM1 resulted in a significant decrease in FOXM1 phosphorylation and transcription of MnSOD and Catalase, leading to cell senescence, indicating that FOXM1 acetylation plays an important role in cellular senescence. Given this, we propose that FOXM1 acetylation can contribute to its phosphorylation by CDK/Cyclin, enhance the transcription of antioxidant genes, and further inhibit cell senescence. We plan to investigate the role of FOXM1 acetylation in cell senescence as well as study the regulation between FOXM1 acetylation and phosphorylation to make sure the mechanism of FOXM1 acetylation control oxidative stress to escape premature senescence. The study will take FOXM1 as a new perspective for revealing the mechanism of ageing, and so as to provide new ideas for the prevention and treatment of tumor and other senile diseases.

细胞周期阻滞是细胞衰老的重要特征，转录因子FOXM1是细胞周期调控的关键因子，研究表明FOXM1能抑制衰老，但机制尚不明确。我们前期研究发现FOXM1能被CBP/p300乙酰化，进而促进肿瘤细胞增殖，目前尚未见乙酰化FOXM1的其他功能报道。本课题预实验显示，FOXM1乙酰化缺失能降低自身磷酸化水平，减弱抗氧化应激基因MnSOD、Catalase转录，促进细胞早老，提示FOXM1乙酰化在调节衰老中起重要作用。据此我们提出假说：FOXM1乙酰化增强CDK/Cyclin对其的磷酸化促进细胞周期，并刺激抗氧化应激基因转录，抑制细胞衰老。本课题拟从分子、细胞及动物等多层次，明确FOXM1乙酰化在细胞衰老中的作用，探索FOXM1乙酰化与磷酸化的作用关系，揭示FOXM1乙酰化抵抗氧化应激诱导的细胞衰老的调控机制。该研究将从FOXM1乙酰化角度揭示细胞衰老分子机制，以期为肿瘤等老年病的防治提供新的思路。