Mammalian Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) and Drosophila Yorkie (Yki) are transcription cofactors of the highly conserved Hippo signaling pathway. It has been long assumed that the YAP/TAZ/Yki signaling drives cell proliferation during organ growth. However, its instructive role in regulating developmentally programmed organ growth, if any, remains elusive. Out-of-context gain of YAP/TAZ/Yki signaling often turns oncogenic. Paradoxically, mechanically strained, and differentiated squamous epithelia display developmentally programmed constitutive nuclear YAP/TAZ/Yki signaling. The unknown, therefore, is how a growth-promoting YAP/TAZ/Yki signaling restricts proliferation in differentiated squamous epithelia. Here, we show that reminiscent of a tumor suppressor, Yki negatively regulates the cell growth–promoting PI3K/Akt/TOR signaling in the squamous epithelia of Drosophila tubular organs. Thus, downregulation of Yki signaling in the squamous epithelium of the adult male accessory gland (MAG) up-regulates PI3K/Akt/TOR signaling, inducing cell hypertrophy, exit from their cell cycle arrest, and, finally, culminating in squamous cell carcinoma (SCC). Thus, blocking PI3K/Akt/TOR signaling arrests Yki loss-induced MAG-SCC. Further, MAG-SCCs, like other lethal carcinomas, secrete a cachectin, Impl2—the Drosophila homolog of mammalian IGFBP7—inducing cachexia and shortening the lifespan of adult males. Moreover, in the squamous epithelium of other tubular organs, like the dorsal trunk of larval tracheal airways or adult Malpighian tubules, downregulation of Yki signaling triggers PI3K/Akt/TOR-induced cell hypertrophy. Our results reveal that Yki signaling plays an instructive, antiproliferative role in the squamous epithelia of tubular organs.

中文翻译：

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Hippo 效应子 Yorkie 是特定果蝇鳞状上皮细胞的抑癌基因


哺乳动物 Yes 相关蛋白 （YAP） 和具有 PDZ 结合基序 （TAZ） 和果蝇约克 （Yki） 的转录共激活因子是高度保守的 Hippo 信号通路的转录辅因子。长期以来，人们一直认为 YAP/TAZ/Yki 信号转导驱动器官生长过程中的细胞增殖。然而，它在调节发育程序性器官生长（如果有的话）中的指导作用仍然难以捉摸。YAP/TAZ/Yki 信号转导的断章取义增益通常会变成致癌的。矛盾的是，机械应变和分化的鳞状上皮细胞显示发育程序化的组成型核 YAP/TAZ/Yki 信号传导。因此，未知数是促进生长的 YAP/TAZ/Yki 信号转导如何限制分化鳞状上皮细胞的增殖。在这里，我们表明 Yki 让人想起肿瘤抑制因子，负向调节果蝇肾小管器官鳞状上皮细胞生长促进 PI3K/Akt/TOR 信号传导。因此，成年男性副腺 （MAG） 鳞状上皮中 Yki 信号的下调上调 PI3K/Akt/TOR 信号传导，诱导细胞肥大，退出细胞周期停滞，最后导致鳞状细胞癌 （SCC）。因此，阻断 PI3K/Akt/TOR 信号传导会阻止 Yki 丢失诱导的 MAG-SCC。此外，MAG-SCC 与其他致命癌一样，分泌恶病质 Impl2（哺乳动物 IGFBP7 的果蝇同源物），诱导恶病质并缩短成年男性的寿命。此外，在其他肾小管器官的鳞状上皮中，如幼虫气管气道的背干或成年马氏小管，Yki 信号的下调会触发 PI3K/Akt/TOR 诱导的细胞肥大。 我们的结果表明，Yki 信号在肾小管器官的鳞状上皮细胞中起着指导性的抗增殖作用。