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CDKAL1 通过组装 eIF4F 翻译起始复合物来驱动癌症干细胞样细胞的维持。

CDKAL1 Drives the Maintenance of Cancer Stem-Like Cells by Assembling the eIF4F Translation Initiation Complex.

机构信息

Department of Cellular Physiology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Okayama, 700-8558, Japan.

Department of Molecular Physiology, Kumamoto University Faculty of Life Sciences, Kumamoto, Kumamoto, 860-0811, Japan.

出版信息

Adv Sci (Weinh). 2023 Apr;10(12):e2206542. doi: 10.1002/advs.202206542. Epub 2023 Feb 14.

DOI:10.1002/advs.202206542
PMID:36786012
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10131790/
Abstract

Cancer stem-like cells (CSCs) have a unique translation mode, but little is understood about the process of elongation, especially the contribution of tRNA modifications to the maintenance of CSCs properties. Here, it is reported that, contrary to the initial aim, a tRNA-modifying methylthiotransferase CDKAL1 promotes CSC-factor SALL2 synthesis by assembling the eIF4F translation initiation complex. CDKAL1 expression is upregulated in patients with worse prognoses and is essential for maintaining CSCs in rhabdomyosarcoma (RMS) and common cancers. Translatome analysis reveals that a group of mRNAs whose translation is CDKAL1-dependent contains cytosine-rich sequences in the 5' untranslated region (5'UTR). Mechanistically, CDKAL1 promotes the translation of such mRNAs by organizing the eIF4F translation initiation complex. This complex formation does not require the enzyme activity of CDKAL1 but requires only the NH -terminus domain of CDKAL1. Furthermore, sites in CDKAL1 essential for forming the eIF4F complex are identified and discovered candidate inhibitors of CDKAL1-dependent translation.

摘要

癌症干细胞 (CSCs) 具有独特的翻译模式，但人们对伸长过程知之甚少，特别是 tRNA 修饰对维持 CSCs 特性的贡献。在这里，据报道，与最初的目的相反，一种 tRNA 修饰甲基转移酶 CDKAL1 通过组装 eIF4F 翻译起始复合物来促进 CSC 因子 SALL2 的合成。CDKAL1 的表达在预后较差的患者中上调，对于维持横纹肌肉瘤 (RMS) 和常见癌症中的 CSCs 是必不可少的。翻译组分析显示，一组依赖 CDKAL1 翻译的 mRNAs 在 5'非翻译区（5'UTR）中含有富含胞嘧啶的序列。从机制上讲，CDKAL1 通过组织 eIF4F 翻译起始复合物来促进这些 mRNA 的翻译。这种复合物的形成不需要 CDKAL1 的酶活性，只需要 CDKAL1 的 NH2-末端结构域。此外，确定了 CDKAL1 中对于形成 eIF4F 复合物至关重要的位点，并发现了 CDKAL1 依赖性翻译的候选抑制剂。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2146/10131790/2013a639e75e/ADVS-10-2206542-g009.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2146/10131790/fc1e5f54d9bf/ADVS-10-2206542-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2146/10131790/4819e4ac2f62/ADVS-10-2206542-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2146/10131790/1130f875e7a7/ADVS-10-2206542-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2146/10131790/2013a639e75e/ADVS-10-2206542-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2146/10131790/609a18b7024d/ADVS-10-2206542-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2146/10131790/0f7a0246b641/ADVS-10-2206542-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2146/10131790/27e5510ba2e7/ADVS-10-2206542-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2146/10131790/50bcff86e06b/ADVS-10-2206542-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2146/10131790/fc1e5f54d9bf/ADVS-10-2206542-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2146/10131790/4819e4ac2f62/ADVS-10-2206542-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2146/10131790/1130f875e7a7/ADVS-10-2206542-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2146/10131790/2013a639e75e/ADVS-10-2206542-g009.jpg

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