Genomic and proteomic analysis reveals a threshold level of MYC required for tumor maintenance.
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.
Shachaf
Catherine M
CM
Department of Medicine and Pathology, Division of Medical Oncology, Stanford University School of Medicine, Stanford University, Stanford, California 94305, USA.
Gentles
Andrew J
AJ
Elchuri
Sailaja
S
Sahoo
Debashis
D
Soen
Yoav
Y
Sharpe
Orr
O
Perez
Omar D
OD
Chang
Maria
M
Mitchel
Dennis
D
Robinson
William H
WH
Dill
David
D
Nolan
Garry P
GP
Plevritis
Sylvia K
SK
Felsher
Dean W
DW
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002453:Cell Cycle / Q000235:genetics; D045744:Cell Line, Tumor; D016000:Cluster Analysis; D018450:Disease Progression; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D023281:Genomics; D051379:Mice; D008822:Mice, Transgenic; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D040901:Proteomics; D016271:Proto-Oncogene Proteins c-myc / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D047368:Tumor Burden
C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc