Enigmatic MYC Conducts an Unfolding Systems Biology Symphony

Division of Hematology, Department of Medicine, and Departments of Cell Biology, Oncology, Pathology, and Molecular Biology & Genetics, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Genes & cancer 06/2010; 1(6):526-531. DOI: 10.1177/1947601910378742
Source: PubMed


The enigmatic MYC oncogene, which participates broadly in cancers, revealed itself recently as the maestro of an unfolding symphony of cell growth, proliferation, death, and metabolism. The study of MYC is arguably most challenging to its students but at the same time exhilarating when MYC reveals its deeply held secrets. It is the excitement of our richer understanding of MYC that is captured in each review of this special issue of Genes & Cancer. Collectively, our deeper understanding of MYC reveals that it is a symphony conductor, controlling a large orchestra of target genes. Although MYC controls many orchestra sections, which are necessary but not sufficient for Myc function, ribosome biogenesis stands out to reveal Myc's primordial function particularly in fruit flies. Because ribosome biogenesis and the associated translational machinery are bioenergetically demanding, Myc's other target genes involved in energy metabolism must be coupled with energy demand to ensure that cells can replicate their genome and produce daughter cells. Normal cells have feedback loops that diminish MYC expression when nutrients are scarce. On the other hand, when deregulated Myc transforms cells, their constitutive bioenergetic demand can trigger cell death when energy is unavailable. This special issue captures the unfolding symphony of MYC-mediated tumorigenesis through reviews that span from a timeline of MYC research, fundamental understanding of how the MYC gene itself is regulated, the study of Myc in model organisms, Myc function, and target genes to translational research in search of new therapeutic modalities for the treatment of cancer.

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Available from: Chi V Dang, Jan 20, 2014
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    • "C-MYC is a highly regulated protein controlling the expression of many genes involved in the cell cycle, cell growth, proliferation and apoptosis12. c-Myc belongs to a family of transcription factors that contain basic helix-loop-helix motifs (b-HLH) and leucine zipper domains3; c-Myc dimerizes with Max45, also a member of the b-HLH family, and potentially tetramerizes (as a dimer of heterodimers) in order to bind to DNA specifically to E-box sequences (CAYGTG). Myc-Max likely carries along transcriptional co-activators or chromatin complexes including their associated histone acetyltransferases or ATPases/helicases5 to the promoters of target genes6. "
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    ABSTRACT: Myc levels are highly regulated and usually low in vivo. Dimerized with Max, it regulates most expressed genes and so directly and indirectly controls most cellular processes. Intranuclear diffusion of a functional c-Myc-eGFP, expressed from its native locus in murine fibroblasts and 3T3 cells or by transient transfection, was monitored using Two Photon Fluorescence Correlation Spectroscopy, revealing concentration and size (mobility) of complexes. With increased c-Myc-eGFP, a very immobile pool saturates as a 'mobile' pool increases. Both pools diffuse too slowly to be free Myc-Max dimers. Following serum stimulation, eGFP-c-Myc accumulated in the presence of the proteasome inhbitor MG132. Stimulating without MG132, Myc peaked at 2.5 hrs, and at steady was ~8 ± 1.3 nM. Inhbiting Myc-Max dimerization by Max-knockdown or drug treatment increased the 'mobile' c-Myc pool size. These results indicate that Myc populates macromolecular complexes of widely heterogenous size and mobility in vivo.
    Full-text · Article · Jun 2013 · Scientific Reports
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    • "Only 10%– 20% of total binding targets were upregulated and 4%–10% were downregulated greater than 2-fold (p < 10 À5 ), leaving the importance of c-Myc binding at most genes undefined (Figure S2H). These complex patterns of binding, expression, and function, typical for studies of this oncogene (Chen et al., 2008; Dang, 2010; Eilers and Eisenman, 2008; Ji et al., 2011), failed to illuminate a principle for Myc action. The discordance of targets between data sets was difficult to rationalize in terms of cell type specificity, stage of activation or function. "
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    ABSTRACT: The c-Myc HLH-bZIP 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 nonlinear 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.
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