Role of Miz1 in the Atr/Chk1 signalling pathway and in Myc-induced apoptosis

原癌基因c-myc在多种人类肿瘤的发生中起着关键作用。了解c-myc在肿瘤发生中的作用需要了解其生物化学和Myc影响细胞生理的蛋白质/蛋白质相互作用。c-myc编码一种转录因子（Myc），它可以激活和抑制转录。Myc与伴侣蛋白Max的异二聚体复合体介导Myc的转录激活。Myc的抑制是由不同的蛋白质复合物介导的；最具特征的是一种三聚体蛋白复合物，包含Myc、Max和锌指蛋白Miz1。我们不了解Myc如何激活和抑制转录的机制。我们最近获得的证据表明，Myc的两个已知的辅助因子，六聚体atp酶Tip48和Tip49，通过Myc和Miz1抑制转录。我们建议遵循这些发现提供的机械线索。其次，我们最近对Myc转录激活的研究已经确定了特定的激活途径，并为介质和p-TEFB复合物在Myc介导的基因激活中的功能作用提供了证据。因此，我们建议确定潜在的生化相互作用，并测试它们在激活和抑制中的作用。

The proto-oncogene c-myc plays a key role in the genesis of a wide variety of human tumours. Understanding how c-myc acts in tumorigenesis requires an understanding of its biochemistry and the protein/protein interactions through which Myc affects cell physiology. c-myc encodes a transcription factor (Myc) that can both activate and repress transcription. A heterodimeric complex of Myc with a partner protein, Max, mediates transcriptional activation by Myc. Repression by Myc is mediated by distinct protein complexes; the best characterized is a trimeric protein complex, which contains Myc, Max, and the zinc finger protein Miz1. We do not understand mechanistically how Myc can both activate and repress transcription. We have recently obtained evidence that two known co-factors of Myc, the hexameric ATPases Tip48 and Tip49, repress transcription through Myc and Miz1. We propose to follow the mechanistic clues provided by these findings. Second, our recent work on transcriptional activation by Myc has defined specific pathways of activation and has provided evidence for a functional role of mediator and p-TEFB complexes in Myc-mediat ed gene activation. We therefore propose to identify the underlying biochemical interactions and test their role in activation and repression.