PDF(Pubmed)
Abstract：
Tumor suppressor genes play critical roles in normal tissue homeostasis, and their dysregulation underlies human diseases including cancer. Besides human genetics, model organisms such as Drosophila have been instrumental in discovering tumor suppressor pathways that were subsequently shown to be highly relevant in human cancer. Here we show that hyperplastic disc (Hyd), one of the first tumor suppressors isolated genetically in Drosophila and encoding an E3 ubiquitin ligase with hitherto unknown substrates, and Lines (Lin), best known for its role in embryonic segmentation, define an obligatory tumor suppressor protein complex (Hyd-Lin) that targets the zinc finger-containing oncoprotein Bowl for ubiquitin-mediated degradation, with Lin functioning as a substrate adaptor to recruit Bowl to Hyd for ubiquitination. Interestingly, the activity of the Hyd-Lin complex is directly inhibited by a micropeptide encoded by another zinc finger gene, drumstick (drm), which functions as a pseudosubstrate by displacing Bowl from the Hyd-Lin complex, thus stabilizing Bowl. We further identify the epigenetic regulator Polycomb repressive complex1 (PRC1) as a critical upstream regulator of the Hyd-Lin-Bowl pathway by directly repressing the transcription of the micropeptide drm Consistent with these molecular studies, we show that genetic inactivation of Hyd, Lin, or PRC1 resulted in Bowl-dependent hyperplastic tissue overgrowth in vivo. We also provide evidence that the mammalian homologs of Hyd (UBR5, known to be recurrently dysregulated in various human cancers), Lin (LINS1), and Bowl (OSR1/2) constitute an analogous protein degradation pathway in human cells, and that OSR2 promotes prostate cancer tumorigenesis. Altogether, these findings define a previously unrecognized tumor suppressor pathway that links epigenetic program to regulated protein degradation in tissue growth control and tumorigenesis.
摘要：
抑癌基因在正常组织稳态中起关键作用，它们的失调是包括癌症在内的人类疾病的基础。除了人类遗传学,果蝇等模型生物在发现肿瘤抑制途径方面发挥了重要作用，这些途径随后被证明与人类癌症高度相关。在这里，我们展示了增生性椎间盘(Hyd)，在果蝇中遗传分离的第一个肿瘤抑制基因之一，编码具有迄今未知底物的E3泛素连接酶，和线（林），以其在胚胎分割中的作用而闻名，定义一种强制性肿瘤抑制蛋白复合物（Hyd-Lin），靶向含锌指的癌蛋白Bowl进行泛素介导的降解，Lin充当底物适配器，将Bowl招募到Hyd进行泛素化。有趣的是,Hyd-Lin复合物的活性被另一个锌指基因编码的微肽直接抑制，鼓槌（drm），通过将Bowl从Hyd-Lin建筑群中移出来充当伪底物，从而稳定碗。我们通过直接抑制微肽drm的转录，进一步确定了表观遗传调节因子Polycomb抑制复合物1（PRC1）作为Hyd-Lin-Bowl途径的关键上游调节因子。我们表明Hyd的遗传失活，林,或PRC1导致体内依赖碗的增生组织过度生长。我们还提供了Hyd的哺乳动物同源物（UBR5，已知在各种人类癌症中反复失调）的证据，Lin(LINS1),和碗（OSR1/2）构成了人类细胞中类似的蛋白质降解途径，OSR2促进前列腺癌的发生。总之,这些发现定义了一个以前未被识别的肿瘤抑制途径,该途径将表观遗传程序与组织生长控制和肿瘤发生过程中调节的蛋白质降解联系起来.
