Journal
CANCER RESEARCH
Volume 68, Issue 13, Pages 5132-5142Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-07-6192
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Funding
- NCI NIH HHS [2P01 CA034233-22A1, R01 CA105102, 1R01 CA89305-01A1, 1R01 CA105102, 3U56 CA112973-03S1, 3R01 CA89305-0351, U56 CA112973, R01 CA089305, P01 CA034233] Funding Source: Medline
- NCRR NIH HHS [U54 RR022241, 1U54RR022241] Funding Source: Medline
- NHLBI NIH HHS [N01-HV-28183, N01HV28183] Funding Source: Medline
- NIAID NIH HHS [R01-AI065824, R01 AI065824] Funding Source: Medline
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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 oil 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.
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