抗肿瘤肽 M1-20 通过 CUL4-DDB1-DCAF1 参与的泛素化作用诱导 CDK1 降解。

IF 4.8 3区医学 Q1 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Cancer gene therapy Pub Date : 2024-11-20 DOI:10.1038/s41417-024-00855-8

Huitong Bu, Chaozhu Pei, Min Ouyang, Yan Chen, Li Yu, Xiaoqin Huang, Yongjun Tan

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引用次数: 0

摘要

CDK1 是一种致癌丝氨酸/苏氨酸激酶，在细胞周期调控中发挥着重要作用。FOXM1 作为 CDK1 的底物之一，需要与 CDK1/CCNB1 复合物结合才能磷酸化依赖性地招募 p300/CBP 辅激活因子来介导转录活性。我们实验室之前的研究发现，一种源自 FOXM1 C 端的新型多肽（M1-20）对癌细胞有很强的抑制作用。在此基础上，为了探索 M1-20 的抑制机制，我们设计了实验，发现 CDK1 是 M1-20 的一个重要靶点。M1-20 通过蛋白酶体途径增强了 CDK1 在 CUL4-DDB1-DCAF1 复合物中的泛素化和降解。M1-20 还能影响 CDK1/CCNB1 复合物的形成。此外，与CDK1抑制剂RO3306相比，M1-20在FVB/N MMTV-PyVT自发性乳腺癌鼠模型中表现出卓越的抑制作用。这些结果表明，M1-20 是一种治疗癌症的潜在 CDK1 抑制剂。

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The antitumor peptide M1-20 induced the degradation of CDK1 through CUL4-DDB1-DCAF1-involved ubiquitination.

CDK1 is an oncogenic serine/threonine kinase known to play an important role in the regulation of the cell cycle. FOXM1, as one of the CDK1 substrates, requires binding of CDK1/CCNB1 complex for phosphorylation-dependent recruitment of p300/CBP coactivators to mediate transcriptional activity. Previous studies from our laboratory found that a novel peptide (M1-20) derived from the C-terminus of FOXM1 exhibited potent inhibitory effects for cancer cells. Based on these proofs and to explore the inhibitory mechanism of M1-20, we designed experiments and found that CDK1 served as an important target of M1-20. M1-20 enhanced the ubiquitination and degradation of CDK1 by CUL4-DDB1-DCAF1 complexes through the proteasome pathway. M1-20 could also affect the formation of CDK1/CCNB1 complexes. In addition, compared to RO3306, a CDK1 inhibitor, M1-20 exhibited excellent inhibitory effects in FVB/N MMTV-PyVT murine model of spontaneous breast cancer. These results suggested that M1-20 was a potential CDK1 inhibitor for the treatment of cancer.

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来源期刊

Cancer gene therapy 医学-生物工程与应用微生物

CiteScore

10.20

自引率

0.00%

发文量

150

审稿时长

4-8 weeks

期刊介绍： Cancer Gene Therapy is the essential gene and cellular therapy resource for cancer researchers and clinicians, keeping readers up to date with the latest developments in gene and cellular therapies for cancer. The journal publishes original laboratory and clinical research papers, case reports and review articles. Publication topics include RNAi approaches, drug resistance, hematopoietic progenitor cell gene transfer, cancer stem cells, cellular therapies, homologous recombination, ribozyme technology, antisense technology, tumor immunotherapy and tumor suppressors, translational research, cancer therapy, gene delivery systems (viral and non-viral), anti-gene therapy (antisense, siRNA & ribozymes), apoptosis; mechanisms and therapies, vaccine development, immunology and immunotherapy, DNA synthesis and repair. Cancer Gene Therapy publishes the results of laboratory investigations, preclinical studies, and clinical trials in the field of gene transfer/gene therapy and cellular therapies as applied to cancer research. Types of articles published include original research articles; case reports; brief communications; review articles in the main fields of drug resistance/sensitivity, gene therapy, cellular therapy, tumor suppressor and anti-oncogene therapy, cytokine/tumor immunotherapy, etc.; industry perspectives; and letters to the editor.