Induction of AP-1 by YAP/TAZ contributes to cell proliferation and organ growth
Induction of AP-1 by YAP/TAZ contributes to cell proliferation and organ growth
复制标题
DOI：
10.1101/gad.331546.119
复制
发表时间：
2020-01-01
影响因子：
10.5
通讯作者：
Guan, Kun-Liang
中科院分区：
文献类型：
--
作者：
Koo, Ja Hyun;Plouffe, Steven W.;Guan, Kun-Liang
yes相关蛋白（YAP）及其与pdz结合基序的同源转录共激活因子（TAZ）是Hippo通路控制细胞生长和器官大小的关键效应子，其失调导致肿瘤发生或肥大。激活后，YAP/TAZ转运进入细胞核并与TEAD转录因子结合，促进转录程序增殖或细胞规格。以AP-1复合体为代表的直接早期基因被快速诱导并控制后期转录程序，在肿瘤发生和器官维持中发挥关键作用。在这里，我们报道了YAP/TAZ直接促进FOS转录，进而促进YAP/TAZ的生物学功能。YAP/TAZ结合到FOS的启动子区域刺激其转录。YAP/TAZ的缺失阻断了对有丝分裂刺激的直接早期基因的诱导。FOS诱导有助于YAP/TAZ下游靶基因的表达。遗传缺失或化学抑制AP-1可抑制yap驱动的癌细胞的生长，如lats1 /2缺陷癌细胞和Ga-q/11突变的葡萄膜黑色素瘤。此外，AP-1抑制几乎完全消除了YAP过表达引起的肝肿大。我们的研究结果揭示了AP-1的即时早期转录与Hippo通路功能之间的前馈相互作用。
Yes-associated protein (YAP) and its homolog transcriptional coactivator with PDZ-binding motif (TAZ) are key effectors of the Hippo pathway to control cell growth and organ size, of which dysregulation yields to tumorigenesis or hypertrophy. Upon activation, YAP/TAZ translocate into the nucleus and bind to TEAD transcription factors to promote transcriptional programs for proliferation or cell specification. Immediate early genes, represented by AP-1 complex, are rapidly induced and control later-phase transcriptional program to play key roles in tumorigenesis and organ maintenance. Here, we report that YAP/TAZ directly promote FOS transcription that in turn contributes to the biological function of YAP/TAZ. YAP/TAZ bind to the promoter region of FOS to stimulate its transcription. Deletion of YAP/TAZ blocks the induction of immediate early genes in response to mitogenic stimuli. FOS induction contributes to expression of YAP/TAZ downstream target genes. Genetic deletion or chemical inhibition of AP-1 suppresses growth of YAP-driven cancer cells, such as Lats1/2-deficient cancer cells as well as Ga-q/11 mutated uveal melanoma. Furthermore, AP-1 inhibition almost completely abrogates the hepatomegaly induced by YAP overexpression. Our findings reveal a feed-forward interplay between immediate early transcription of AP-1 and Hippo pathway function.