MYC overexpression has been implicated in the
pathogenesis of most types of human cancers.
MYC is likely to contribute to
tumorigenesis by its effects on global
gene expression. Previously, we have shown that the loss of
MYC overexpression is sufficient to reverse
tumorigenesis. Here, we show that there is a precise threshold level of
MYC expression required for maintaining the
tumor phenotype, whereupon there is a switch from a
gene expression program of proliferation to a state of proliferative arrest and
apoptosis.
Oligonucleotide microarray analysis and quantitative
PCR were used to identify changes in expression in 3,921 genes, of which 2,348 were down-regulated and 1,573 were up-regulated. Critical changes in
gene expression occurred at or near the
MYC threshold, including genes implicated in the regulation of the G(1)-S and G(2)-
M cell cycle checkpoints and
death receptor/
apoptosis signaling. Using two-dimensional
protein analysis followed by
mass spectrometry, phospho-flow fluorescence-activated cell sorting, and
antibody arrays, we also identified changes at the protein level that contributed to MYC-dependent
tumor regression. Proteins involved in
mRNA translation decreased below threshold levels of
MYC. Thus, at the
MYC threshold, there is a loss of its ability to maintain
tumorigenesis, with associated shifts in gene and
protein expression that reestablish
cell cycle checkpoints, halt protein translation, and promote
apoptosis.
