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

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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.