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PRL3-DDX21 对内溶酶体基因的转录调控限制了黑素细胞干细胞的分化。

PRL3-DDX21 Transcriptional Control of Endolysosomal Genes Restricts Melanocyte Stem Cell Differentiation.

机构信息

MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Crewe Road South, Edinburgh EH4 2XU, UK; Cancer Research UK Edinburgh Centre, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK.

MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Crewe Road South, Edinburgh EH4 2XU, UK; Cancer Research UK Edinburgh Centre, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK; Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.

出版信息

Dev Cell. 2020 Aug 10;54(3):317-332.e9. doi: 10.1016/j.devcel.2020.06.013. Epub 2020 Jul 10.

DOI:10.1016/j.devcel.2020.06.013
PMID:32652076
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7435699/
Abstract

Melanocytes, replenished throughout life by melanocyte stem cells (MSCs), play a critical role in pigmentation and melanoma. Here, we reveal a function for the metastasis-associated phosphatase of regenerating liver 3 (PRL3) in MSC regeneration. We show that PRL3 binds to the RNA helicase DDX21, thereby restricting productive transcription by RNAPII at master transcription factor (MITF)-regulated endolysosomal vesicle genes. In zebrafish, this mechanism controls premature melanoblast expansion and differentiation from MSCs. In melanoma patients, restricted transcription of this endolysosomal vesicle pathway is a hallmark of PRL3-high melanomas. Our work presents the conceptual advance that PRL3-mediated control of transcriptional elongation is a differentiation checkpoint mechanism for activated MSCs and has clinical relevance for the activity of PRL3 in regenerating tissue and cancer.

摘要

黑素细胞由黑素干细胞 (MSCs) 终身补充，在色素沉着和黑色素瘤中发挥关键作用。在这里，我们揭示了肝再生磷酸酶 3 (PRL3) 在 MSC 再生中的转移相关功能。我们表明 PRL3 与 RNA 解旋酶 DDX21 结合，从而限制了 RNA 聚合酶 II 在主要转录因子 (MITF) 调节的内溶酶体囊泡基因上的有效转录。在斑马鱼中，这种机制控制黑素前体细胞的过早扩张和从 MSCs 分化。在黑色素瘤患者中，内溶酶体囊泡途径的受限转录是 PRL3 高黑色素瘤的标志。我们的工作提出了一个概念上的进展，即 PRL3 介导的转录延伸控制是激活的 MSC 的分化检查点机制，并且对于 PRL3 在再生组织和癌症中的活性具有临床意义。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/24e5/7435699/d354c50df0c8/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/24e5/7435699/c79e836e8b09/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/24e5/7435699/e2efd52d8645/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/24e5/7435699/1cde9d163a02/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/24e5/7435699/164441938ef1/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/24e5/7435699/0bf0565e2bc3/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/24e5/7435699/4f21c99f5ca0/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/24e5/7435699/6edd23a15402/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/24e5/7435699/d354c50df0c8/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/24e5/7435699/c79e836e8b09/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/24e5/7435699/e2efd52d8645/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/24e5/7435699/1cde9d163a02/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/24e5/7435699/164441938ef1/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/24e5/7435699/0bf0565e2bc3/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/24e5/7435699/4f21c99f5ca0/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/24e5/7435699/6edd23a15402/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/24e5/7435699/d354c50df0c8/gr7.jpg

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本文引用的文献

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Melanoma plasticity and phenotypic diversity: therapeutic barriers and opportunities.
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