Deregulated expression of MYC oncogenes is a common denominator of cancer. The creation of c-myc and N-myc knockout mice established that their functions are required for cell cycle traverse of distinct cell types, and for embryonic development. Conversely, deregulated expression of Myc oncoproteins is sufficient to provoke entry of quiescent cells into cycle, suggesting this is why these transcription factors are activated in cancer. Expression profiling has demonstrated that Myc provokes widespread changes in gene expression, yet the precise mechanism(s) by which this broad response is orchestrated is unclear. Furthermore, the exact reasons why c-myc -/- and N-myc /- embryos fail have not been resolved. The experiments of this proposal address these central issues, and our studies support the hypothesis that Myc oncoproteins regulate such a pervasive genomic response by acting as essential regulators of cytokines critical for cell cycle traverse and development. Specifically, we have shown that c-Myc is required for vasculogenesis and angiogenesis during development and during tumor progression, whereas N-Myc is required for primitive and definitive erythropoiesis. Myc oncoproteins associate with Max to either activate or repress the transcription of target genes. A clearer understanding of the developmental roles of c-Myc and N-Myc requires identification of their target progenitor cells and establishing which transcription functions of Myc are required for its biologic activities. Using genetic approaches, the experiments in Specific Aim #1 will define the precise target cells and functions of N-Myc and c-Myc required for embryonic erythropoiesis and vasculogenesis, and for tumor angiogenesis. Loss of c-Myc expression in embryonic endothelial cells is associated with coordinate and profound changes in the expression of a large cadre of angiogenic factors required for growth and modeling of the vasculature, and these same alterations in c-myc -/- embryonic stem (ES) cells compromises their ability to form tumors in immune compromised mice, by blocking tumor angiogenesis. Our preliminary studies suggest a novel mechanism by which Myc regulates the expression of these cytokines. Thus, experiments in Specific Aim #2 will determine the mechanism by which c-Myc regulates the expression of cytokines essential for vasculogenesis and angiogenesis. Heretofore Myc functions have been thought to be antagonized by a dedicated group of related transcription factors, the Mad family and Mnt, which also associate with Max, yet repress Myc target genes. Our new findings have rather suggested a new model in which Myc functions as an oncogene by virtue of its ability to antagonize the function of Mnt, which we have shown functions as a tumor suppressor.
In Specific Aim #3 we test this hypothesis by addressing the role of Mnt as the key regulator of the N-Myc and e- Myc responses that orchestrate embryonic erythropoiesis and vasculogenesis, and tumor angiogenesis.
| Rounbehler, Robert J; Fallahi, Mohammad; Yang, Chunying et al. (2012) Tristetraprolin impairs myc-induced lymphoma and abolishes the malignant state. Cell 150:563-74 |
| Ji, Hongkai; Wu, George; Zhan, Xiangcan et al. (2011) Cell-type independent MYC target genes reveal a primordial signature involved in biomass accumulation. PLoS One 6:e26057 |
| Rodrigues, Claudia O; Nerlick, Steve T; White, Elsie L et al. (2008) A Myc-Slug (Snail2)/Twist regulatory circuit directs vascular development. Development 135:1903-11 |
| Nilsson, Jonas A; Cleveland, John L (2004) Mnt: master regulator of the Max network. Cell Cycle 3:588-90 |
| Nilsson, Jonas A; Maclean, Kirsteen H; Keller, Ulrich B et al. (2004) Mnt loss triggers Myc transcription targets, proliferation, apoptosis, and transformation. Mol Cell Biol 24:1560-9 |
| Nilsson, Jonas A; Nilsson, Lisa M; Keller, Ulrich et al. (2004) Id2 is dispensable for myc-induced lymphomagenesis. Cancer Res 64:7296-301 |
| Jeffers, John R; Parganas, Evan; Lee, Youngsoo et al. (2003) Puma is an essential mediator of p53-dependent and -independent apoptotic pathways. Cancer Cell 4:321-8 |
| Alt, Jodi R; Greiner, Timothy C; Cleveland, John L et al. (2003) Mdm2 haplo-insufficiency profoundly inhibits Myc-induced lymphomagenesis. EMBO J 22:1442-50 |
| Baudino, Troy A; Maclean, Kirsteen H; Brennan, Jennifer et al. (2003) Myc-mediated proliferation and lymphomagenesis, but not apoptosis, are compromised by E2f1 loss. Mol Cell 11:905-14 |
| Zindy, Frederique; Williams, Richard T; Baudino, Troy A et al. (2003) Arf tumor suppressor promoter monitors latent oncogenic signals in vivo. Proc Natl Acad Sci U S A 100:15930-5 |
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