Abstract IA01: Myc functions within a transcriptional regulatory network

Abstract

Abstract In this talk I will explore the idea that Myc proteins do not act independently, but rather function in the context of a larger network of transcription factors. This network can be considered as having two interconnected branches, each requiring heterodimerization with either Max or the Max-like protein, Mlx. Max forms heterodimers with Myc and Mxd family proteins (including Mnt and Mga), while Mlx heterodimerizes with the large BHLHZ proteins MondoA and ChREBP. A subset of Mxd proteins also heterodimerize with Mlx. Based on our current knowledge of the organization and the functions of its different components, it is possible to view the network as a transcriptional module that responds to and integrates extracellular and intracellular stimuli in order to modulate gene expression programs that ultimately act to affect cellular behavior. We can consider the three sub-families within the network, Myc, Mxd, and MondoA/ChREBP, as being responsive to mitogenic signaling, growth arrest/differentiation signals, and nutrient availability, respectively. The transcriptional response mediated by these factors is further modified by their ability to interact with other transcriptional regulators (e.g. Miz1) and to recruit chromatin modifying factors. Importantly, the notion of an extended Max/Mlx network is likely to go beyond the simple wiring diagram described above. For example functional interactions have been described among network members such as the antagonism at molecular and biological levels between Myc and Mxd proteins. Recently we have shown that the metabolic reprograming induced by deregulated Myc proteins in several distinct tumor types is cooperatively regulated by, and dependent on, MondoA-Mlx. The transcriptional changes mediated by Myc-Max and MondoA-Mlx are critical for tumor cell survival. Analysis of Myc's activities within the context of the extended network, as well as the dynamics of the network as a whole, may provide insights into the molecular basis and the consequences of Myc deregulation in the etiology of cancer and new approaches to inhibit Myc. Citation Format: Robert Eisenman. Myc functions within a transcriptional regulatory network. [abstract]. In: Proceedings of the AACR Special Conference on Myc: From Biology to Therapy; Jan 7-10, 2015; La Jolla, CA. Philadelphia (PA): AACR; Mol Cancer Res 2015;13(10 Suppl):Abstract nr IA01.