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, 一个 DNA 损伤反应基因，对于 Notch 介导的鳞状细胞分化诱导是必需的。

, a DNA damage response gene, is required for Notch-mediated induction of squamous cell differentiation.

机构信息

Department of Pathology, Brigham and Women's Hospital, and Harvard Medical School, Boston, United States.

Bioinfo, Plantagenet, Canada.

出版信息

Elife. 2020 Sep 16;9:e58081. doi: 10.7554/eLife.58081.

DOI:10.7554/eLife.58081
PMID:32936072
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7529455/
Abstract

Notch signaling regulates squamous cell proliferation and differentiation and is frequently disrupted in squamous cell carcinomas, in which Notch is tumor suppressive. Here, we show that conditional activation of Notch in squamous cells activates a context-specific gene expression program through lineage-specific regulatory elements. Among direct Notch target genes are multiple DNA damage response genes, including , which we show is required for Notch-induced differentiation of squamous carcinoma cells and TERT-immortalized keratinocytes. is epistatic to , a gene that encodes the PP2A B55α subunit, which we show interacts with IER5 in cells and in purified systems. Thus, Notch and DNA-damage response pathways converge in squamous cells on common genes that promote differentiation, which may serve to eliminate damaged cells from the proliferative pool. We further propose that crosstalk involving Notch and PP2A enables tuning and integration of Notch signaling with other pathways that regulate squamous differentiation.

摘要

Notch 信号通路调节鳞状细胞的增殖和分化，在鳞状细胞癌中经常受到干扰，而 Notch 在鳞状细胞癌中是肿瘤抑制因子。在这里，我们表明，条件性激活鳞状细胞中的 Notch 通过谱系特异性调节元件激活特定于上下文的基因表达程序。直接的 Notch 靶基因包括多个 DNA 损伤反应基因，包括 ，我们表明它是 Notch 诱导鳞状癌细胞和 TERT 永生化角质形成细胞分化所必需的。是 的上位基因，编码蛋白磷酸酶 2A 的 B55α 亚基，我们表明它在细胞中和纯化系统中与 IER5 相互作用。因此，Notch 和 DNA 损伤反应途径在鳞状细胞中汇聚到共同的基因上，这些基因促进分化，这可能有助于将受损细胞从增殖池中清除。我们进一步提出，涉及 Notch 和 PP2A 的串扰使 Notch 信号与其他调节鳞状细胞分化的途径的调谐和整合成为可能。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7413/7529455/9fe1a4aae198/elife-58081-fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7413/7529455/1b99e2024635/elife-58081-fig1.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7413/7529455/fdf27c5c9148/elife-58081-fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7413/7529455/22401e6c5797/elife-58081-fig2-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7413/7529455/c6476f9efe9d/elife-58081-fig2-figsupp2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7413/7529455/931d4d7d9c4b/elife-58081-fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7413/7529455/0a61f63cb2e6/elife-58081-fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7413/7529455/887b92e6212e/elife-58081-fig4-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7413/7529455/41ff97ba5829/elife-58081-fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7413/7529455/544230a9c14f/elife-58081-fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7413/7529455/9fe1a4aae198/elife-58081-fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7413/7529455/1b99e2024635/elife-58081-fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7413/7529455/db673ffda744/elife-58081-fig1-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7413/7529455/91d832ef84f5/elife-58081-fig1-figsupp2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7413/7529455/9bf762f5be77/elife-58081-fig1-figsupp3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7413/7529455/fdf27c5c9148/elife-58081-fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7413/7529455/22401e6c5797/elife-58081-fig2-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7413/7529455/c6476f9efe9d/elife-58081-fig2-figsupp2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7413/7529455/931d4d7d9c4b/elife-58081-fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7413/7529455/0a61f63cb2e6/elife-58081-fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7413/7529455/887b92e6212e/elife-58081-fig4-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7413/7529455/41ff97ba5829/elife-58081-fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7413/7529455/544230a9c14f/elife-58081-fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7413/7529455/9fe1a4aae198/elife-58081-fig7.jpg

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