Supraphysiological MYC levels are oncogenic. Originally considered a typical transcription factor recruited to E-boxes (CACGTG), another theory posits MYC a global amplifier increasing output at all active promoters. Both models rest on large-scale genome-wide ”-omics’. Because the assumptions, statistical parameter and model choice dictates the ‘-omic’ results, whether MYC is a general or specific transcription factor remains controversial. Therefore, an orthogonal series of experiments interrogated MYC’s effect on the expression of synthetic reporters. Dose-dependently, MYC increased output at minimal promoters with or without an E-box. Driving minimal promoters with exogenous (glucocorticoid receptor) or synthetic transcription factors made expression more MYC-responsive, effectively increasing MYC-amplifier gain. Mutations of conserved MYC-Box regions I and II impaired amplification, whereas MYC-box III mutations delivered higher reporter output indicating that MBIII limits over-amplification. Kinetic theory and experiments indicate that MYC activates at least two steps in the transcription-cycle to explain the non-linear amplification of transcription that is essential for global, supraphysiological transcription in cancer.
Bibliographical noteFunding Information:
This work was supported by the Intramural Research Programs of the National Cancer Institute (Center for Cancer Research) and the National Institute of Diabetes and Digestive and Kidney Diseases. We thank the NHLBI Flow Cytometry Core and for DNA sequencing the CCR Genomics Core. Author Contributions: ZN, CG and designed and conducted experiments and analyzed data, SKD designed and conducted experiments, CCC analyzed data and wrote the manuscript, EB, SSS and DL designed experiments, analyzed data and wrote the manuscript.
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PubMed: MeSH publication types
- Journal Article
- Research Support, N.I.H., Extramural