The Myc protein family is profoundly involved in initiation, progression, and survival of a wide range of human cancers. Understanding the critical tumor-specific pathways through which Myc drives neoplasia presents a major hurdle in inhibiting Myc-driven cancers. Myc is a transcription factor that forms a heterodimer with the Max protein. The Myc-Max dimer binds DNA and broadly regulates expression of large numbers of genes involved in cell growth and division. When deregulated, Myc-Max alters the levels and timing of gene expression leading to multiple metabolic and growth related changes that support tumor progression. Importantly, recent studies have shown that Myc-Max does not function alone, but is part of a larger """"""""network"""""""" of protein interactions, the Max/Mlx network. Mlx is a Max-like protein that heterodimerizes with the transcription factors MondoA and ChREBP to regulate genes primarily involved in cell metabolism. The Max and Mlx arms of the network are distinct yet connected. While much research has focused on these transcription factors, we lack a clear understanding of how the extended Max-Mlx network is functionally integrated and what roles this larger network plays in normal cellular processes and tumorigenesis. The objectives of this proposal are to reveal the transcriptional circuitry and the functional dependencies within the Max/Mlx network that enable Myc activity in neoplastic cells. These ideas are based on our preliminary data indicating a specific and critical role for MondoA-Mlx in the metabolism and survival of Myc-driven tumors. These studies reveal cross-talk and functional dependencies among factors within the larger network. The central hypothesis is that the Max and Mlx arms of the network cooperate to link Myc to nutrient sensing thereby serving to augment metabolic flexibility within the evolving tumor. We propose two specific aims: (1) Define the molecular mechanisms through which Myc-induced metabolic reprograming is enabled by the extended Max-Mlx transcription network;(2) Employ mouse genetics to reveal physiological and molecular functions of Mlx and Max.
Aim 1 will use metabolomics and ChIP-Seq to define metabolic pathways and genes that are co-regulated by Myc-Max and MondoA-Mlx in human neuroblastomas. This information will in turn be used to identify potential targets for specific inhibitors in a wide spectrum of tumor types.
Aim 2 will employ our conditional targeted deletions of mlx and of max to define their roles in lymphoid development, in the etiology of leukemia, and in orchestrating genomic binding by the transcription factors within the extended network. The rationale for the proposal is that it will reveal novel pathways and modes of regulation that will provide us with new and more sensitive targets for tumor therapy.
The Myc protein is an essential regulator of growth in all normal cells, but in many cancers Myc is overactive and supports high rates of growth needed for tumor progression. In this proposal we will determine precisely what aspects of growth are controlled by overactive Myc and what other factors Myc depends on for its ability to drive tumor progression. This research is relevant to public health because it will ultimately lead a better understanding of the causes for cancer and to new targets suitable for highly specific cancer therapies.
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| Poudel, Kumud R; Roh-Johnson, Minna; Su, Allen et al. (2018) Competition between TIAM1 and Membranes Balances Endophilin A3 Activity in Cancer Metastasis. Dev Cell 45:738-752.e6 |
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| Kanatsu-Shinohara, Mito; Tanaka, Takashi; Ogonuki, Narumi et al. (2016) Myc/Mycn-mediated glycolysis enhances mouse spermatogonial stem cell self-renewal. Genes Dev 30:2637-2648 |
| Scognamiglio, Roberta; Cabezas-Wallscheid, Nina; Thier, Marc Christian et al. (2016) Myc Depletion Induces a Pluripotent Dormant State Mimicking Diapause. Cell 164:668-80 |
| Sanchez, Erica L; Carroll, Patrick A; Thalhofer, Angel B et al. (2015) Latent KSHV Infected Endothelial Cells Are Glutamine Addicted and Require Glutaminolysis for Survival. PLoS Pathog 11:e1005052 |
| Gu, Haiwei; Du, Jianhai; Carnevale Neto, Fausto et al. (2015) Metabolomics method to comprehensively analyze amino acids in different domains. Analyst 140:2726-34 |
| Diolaiti, Daniel; McFerrin, Lisa; Carroll, Patrick A et al. (2015) Functional interactions among members of the MAX and MLX transcriptional network during oncogenesis. Biochim Biophys Acta 1849:484-500 |
| Carroll, Patrick A; Eisenman, Robert N (2015) Growing old with Myc. Cell 160:365-6 |
| Carroll, Patrick A; Diolaiti, Daniel; McFerrin, Lisa et al. (2015) Deregulated Myc requires MondoA/Mlx for metabolic reprogramming and tumorigenesis. Cancer Cell 27:271-85 |
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