Distinct thresholds govern Myc's biological output in vivo.
Deregulated Myc triggers a variety of intrinsic tumor suppressor programs that serve to restrain Myc's oncogenic potential. Since Myc activity is also required for normal cell proliferation, activation of intrinsic tumor suppression must be triggered only when Myc signaling is oncogenic. However, how cells discriminate between normal and oncogenic Myc is unknown. Here we show that distinct threshold levels of Myc govern its output in vivo: low levels of deregulated Myc are competent to drive ectopic proliferation of somatic cells and oncogenesis, but activation of the apoptotic and ARF/p53 intrinsic tumor surveillance pathways requires Myc overexpression. The requirement to keep activated oncogenes at a low level to avoid engaging tumor suppression is likely an important selective pressure governing the early stages of tumor microevolution.
Murphy
Daniel J
DJ
Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA.
Junttila
Melissa R
MR
Pouyet
Laurent
L
Karnezis
Anthony
A
Shchors
Ksenya
K
Bui
Duyen A
DA
Brown-Swigart
Lamorna
L
Johnson
Leisa
L
Evan
Gerard I
GI
D000818:Animals; D017209:Apoptosis; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D005347:Fibroblasts / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D005838:Genotype; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D016271:Proto-Oncogene Proteins c-myc; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53