Analysis of the c-MYC-associated protein ZNF281

点击翻译按钮获取中文摘要

The prototypic c-MYC oncogene encodes a transcription factor which is required and sufficient for the induction of cellular proliferation. The activity of the c-MYC protein is regulated and mediated by numerous interacting proteins. Via a proteomic approach we recently identified the zinc-finger protein ZNF281/ZBP-99 as a c-MYC interacting protein. ZNF281 directly binds to the functionally important MYC-Box II domain. Since ZNF281 has a comparatively high affinity to c-MYC, we expect that this interaction is of great importance for the function of c-MYC. Interestingly, ectopic ZNF281 represses c-MYC-mediated gene activation and inhibits cell proliferation. In this proposal we intend to determine in which molecular context the c-MYC/ZNF281 interaction is functionally relevant. Therefore, the upstream signaling of ZNF281 will be characterized by proteomic identification and functional analysis of ZNF281-associated proteins. In addition, the role of the MYC/ZNF281 interaction in gene regulation will be analyzed. Therefore, differential gene regulation and promoter occupation of ZNF281 and c-MYC after activation of ZNF281, c-MYC or a combination of both will be compared on a genome-wide scale. This comparison will allow the identification of genes co-regulated by both factors. Subsequently, functional analysis of such genes will be performed to determine their role in mediating the effect of a ZNF281/c-MYC complex on cells.