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通过多个位点磷酸化和脯氨酸顺/反异构化激活致癌转录因子 B-Myb。

Activation of the oncogenic transcription factor B-Myb via multisite phosphorylation and prolyl cis/trans isomerization.

机构信息

Institute for Biochemistry Westfälische-Wilhelms-Universität, D-48149 Münster, Germany.

Friedrich Miescher Institute for Biomedical Research, Maulbeerstr. 66, CH-4058 Basel, Switzerland.

出版信息

Nucleic Acids Res. 2019 Jan 10;47(1):103-121. doi: 10.1093/nar/gky935.

DOI:10.1093/nar/gky935
PMID:30321399
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6326806/
Abstract

The oncogenic transcription factor B-Myb is an essential regulator of late cell cycle genes whose activation by phosphorylation is still poorly understood. We describe a stepwise phosphorylation mechanism of B-Myb, which involves sequential phosphorylations mediated by cyclin-dependent kinase (Cdk) and Polo-like kinase 1 (Plk1) and Pin1-facilitated peptidyl-prolyl cis/trans isomerization. Our data suggest a model in which initial Cdk-dependent phosphorylation of B-Myb enables subsequent Pin1 binding and Pin1-induced conformational changes of B-Myb. This, in turn, initiates further phosphorylation of Cdk-phosphosites, enabling Plk1 docking and subsequent Plk1-mediated phosphorylation of B-Myb to finally allow B-Myb to stimulate transcription of late cell cycle genes. Our observations reveal novel mechanistic hierarchies of B-Myb phosphorylation and activation and uncover regulatory principles that might also apply to other Myb family members. Strikingly, overexpression of B-Myb and of factors mediating its activation strongly correlates with adverse prognoses for tumor patients, emphasizing B-Myb's role in tumorigenesis.

摘要

致癌转录因子 B-Myb 是晚期细胞周期基因的重要调节因子，其磷酸化激活仍知之甚少。我们描述了 B-Myb 的逐步磷酸化机制，该机制涉及由细胞周期蛋白依赖性激酶 (Cdk) 和 Polo 样激酶 1 (Plk1) 介导的顺序磷酸化以及 Pin1 促进的肽脯氨酰顺/反式异构化。我们的数据表明了一个模型，其中 B-Myb 的初始 Cdk 依赖性磷酸化使随后的 Pin1 结合和 Pin1 诱导的 B-Myb 构象变化成为可能。反过来，这又引发了 Cdk 磷酸化位点的进一步磷酸化，使 Plk1 对接并随后进行 Plk1 介导的 B-Myb 磷酸化，最终使 B-Myb 能够刺激晚期细胞周期基因的转录。我们的观察结果揭示了 B-Myb 磷酸化和激活的新机制层次，并揭示了可能也适用于其他 Myb 家族成员的调节原则。引人注目的是，B-Myb 的过表达和介导其激活的因子与肿瘤患者的不良预后强烈相关，强调了 B-Myb 在肿瘤发生中的作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eb4e/6326806/0084d4247d69/gky935fig11.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eb4e/6326806/1fff5da82341/gky935fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eb4e/6326806/f6985bff519c/gky935fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eb4e/6326806/c2283941dd0f/gky935fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eb4e/6326806/b891bb35126b/gky935fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eb4e/6326806/ca5e9e95676e/gky935fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eb4e/6326806/7bde2fa6316a/gky935fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eb4e/6326806/1cbc14d38ef2/gky935fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eb4e/6326806/225bc2ded627/gky935fig8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eb4e/6326806/ce939bb2c0f9/gky935fig9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eb4e/6326806/f439634175c4/gky935fig10.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eb4e/6326806/0084d4247d69/gky935fig11.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eb4e/6326806/1fff5da82341/gky935fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eb4e/6326806/f6985bff519c/gky935fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eb4e/6326806/c2283941dd0f/gky935fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eb4e/6326806/b891bb35126b/gky935fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eb4e/6326806/ca5e9e95676e/gky935fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eb4e/6326806/7bde2fa6316a/gky935fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eb4e/6326806/1cbc14d38ef2/gky935fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eb4e/6326806/225bc2ded627/gky935fig8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eb4e/6326806/ce939bb2c0f9/gky935fig9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eb4e/6326806/f439634175c4/gky935fig10.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eb4e/6326806/0084d4247d69/gky935fig11.jpg

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本文引用的文献

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2
MYBL2 (B-Myb): a central regulator of cell proliferation, cell survival and differentiation involved in tumorigenesis.MYBL2（B-Myb）：一种参与肿瘤发生的细胞增殖、细胞存活和分化的核心调节因子。
Cell Death Dis. 2017 Jun 22;8(6):e2895. doi: 10.1038/cddis.2017.244.
3
CDK Substrate Phosphorylation and Ordering the Cell Cycle.
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4
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Sci Rep. 2024 Apr 2;14(1):7733. doi: 10.1038/s41598-024-58424-w.
5
RNA mC modification upregulates E2F1 expression in a manner dependent on YBX1 phase separation and promotes tumor progression in ovarian cancer.mC 修饰的 RNA 通过依赖于 YBX1 相分离的方式上调 E2F1 的表达，并促进卵巢癌的肿瘤进展。
Exp Mol Med. 2024 Mar;56(3):600-615. doi: 10.1038/s12276-024-01184-4. Epub 2024 Mar 1.
6
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Int J Biol Sci. 2022 Jun 25;18(10):4151-4170. doi: 10.7150/ijbs.72386. eCollection 2022.
7
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5
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8
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9
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