Katrina A Mitchell, Joseph H A Vissers, Jonathan M Pojer, Elliot Brooks, Abdul Jabbar Saiful Hilmi, Anthony T Papenfuss, Jan Schröder, Kieran F Harvey
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引用次数: 0
摘要
上皮器官通过积极清除有缺陷的细胞(如失去顶基极性的细胞)来保持其完整性并防止肿瘤的发生。在这里,我们确定了两个关键信号通路--Jun-N-末端激酶(JNK)和Hippo--的转录因子如何通过控制一组重叠的靶基因的转录来调节上皮的完整性。靶向 DamID 实验显示,在黑腹果蝇眼睛的增殖细胞中,AP-1 转录因子 Jun 和 Hippo 通路转录调节因子 Yorkie 和 Scalloped 与促进器官生长的一系列共同靶基因结合。在有缺陷的肿瘤细胞中,AP-1 转录因子与 C 端结合蛋白(CtBP)共抑制因子一起抑制生长基因的转录。如果 AP-1/CtBP 对基因的抑制失效,肿瘤就会在约基/扇贝蛋白的驱动下生长。因此,AP-1/CtBP 通过与 Yorkie/Scalloped 并行抑制共同转录组的表达,消除了有缺陷的细胞,防止了肿瘤的发生。这些发现为维护上皮完整性和抑制肿瘤提供了新的思路。
The JNK and Hippo pathways control epithelial integrity and prevent tumor initiation by regulating an overlapping transcriptome.
Epithelial organs maintain their integrity and prevent tumor initiation by actively removing defective cells, such as those that have lost apicobasal polarity. Here, we identify how transcription factors of two key signaling pathways-Jun-N-terminal kinase (JNK) and Hippo-regulate epithelial integrity by controlling transcription of an overlapping set of target genes. Targeted DamID experiments reveal that, in proliferating cells of the Drosophila melanogaster eye, the AP-1 transcription factor Jun and the Hippo pathway transcription regulators Yorkie and Scalloped bind to a common suite of target genes that promote organ growth. In defective neoplastic cells, AP-1 transcription factors repress transcription of growth genes together with the C-terminal binding protein (CtBP) co-repressor. If gene repression by AP-1/CtBP fails, neoplastic tumor growth ensues, driven by Yorkie/Scalloped. Thus, AP-1/CtBP eliminates defective cells and prevents tumor initiation by acting in parallel to Yorkie/Scalloped to repress expression of a shared transcriptome. These findings shed new light on the maintenance of epithelial integrity and tumor suppression.
期刊介绍:
Current Biology is a comprehensive journal that showcases original research in various disciplines of biology. It provides a platform for scientists to disseminate their groundbreaking findings and promotes interdisciplinary communication. The journal publishes articles of general interest, encompassing diverse fields of biology. Moreover, it offers accessible editorial pieces that are specifically designed to enlighten non-specialist readers.