The c-Myc bHLH-ZIP protein has been implicated in physiological or pathological growth, proliferation, apoptosis, metabolism and differentiation at the cellular, tissue or organismal levels via regulation of numerous target genes. No principle yet unifies Myc action due partly to an incomplete inventory and functional accounting of Myc?s targets. To observe Myc target expression and function in a system where Myc is temporally and physiologically regulated, the transcriptomes and the genome-wide distributions of Myc, RNA polymerase II and chromatin modifications were compared during lymphocyte activation and in ES cells as well. A remarkably simple rule emerged from this quantitative analysis: Myc is not an on-off specifier of gene activity, but is a non-linear amplifier of expression, acting universally at active genes, except for immediate early genes that are strongly induced before Myc. This rule of Myc action explains the vast majority of Myc biology observed in literature. Current investigations are exploring the molecular mechanisms exploited by MYC to augment gene expression and to demonstrate how small changes in MYC levels or short pulses of MYC activity may modify the growth of normal and neoplastic cells. The theory that MYC is an amplifier was derived from genome-wide studies of MYC and RNA polymerase binding to chromatin in vivo and RNA expression. We are now testing this theory with an orthogonal set of methods and experiments based on transfections and synthetic biology that thus far fully confirm the predictions of the amplifier model. We are exploring a possible a biochemccal mechanism that unifies MYC's diverse activities and that has therapeutic implications.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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National Cancer Institute Division of Basic Sciences
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Zheng, Ying; Levens, David (2017) Enhancers not required. Elife 6:
Zheng, Ying; Levens, David (2016) Tuning the MYC response. Elife 5:
Guo, Linna; Zaysteva, Olga; Nie, Zuqin et al. (2016) Defining the essential function of FBP/KSRP proteins: Drosophila Psi interacts with the mediator complex to modulate MYC transcription and tissue growth. Nucleic Acids Res :
Kaur, Sukhbir; Soto-Pantoja, David R; Stein, Erica V et al. (2013) Thrombospondin-1 signaling through CD47 inhibits self-renewal by regulating c-Myc and other stem cell transcription factors. Sci Rep 3:1673
Levens, David; Aplan, Peter D (2013) Notching up MYC gives a LIC. Cell Stem Cell 13:8-9
Rosales, Tilman; Nie, Zuqin; Kapoor, Varun et al. (2013) Partition of Myc into Immobile vs. Mobile Complexes within Nuclei. Sci Rep 3:1953
Matsushita, Kazuyuki; Tamura, Mai; Tanaka, Nobuko et al. (2013) Interactions between SAP155 and FUSE-binding protein-interacting repressor bridges c-Myc and P27Kip1 expression. Mol Cancer Res 11:689-98
Lovén, Jakob; Orlando, David A; Sigova, Alla A et al. (2012) Revisiting global gene expression analysis. Cell 151:476-82
Nie, Zuqin; Hu, Gangqing; Wei, Gang et al. (2012) c-Myc is a universal amplifier of expressed genes in lymphocytes and embryonic stem cells. Cell 151:68-79