MYC affects normal and neoplastic cell proliferation by altering
gene expression, but the precise pathways remain unclear. We used
oligonucleotide microarray analysis of 6,416 genes and expressed
sequence tags to determine changes in gene expression caused by
activation of c-MYC in primary human fibroblasts. In these experiments,
27 genes were consistently induced, and 9 genes were repressed.
The identity of the genes revealed that MYC may affect many aspects
of cell physiology altered in transformed cells: cell growth,
cell cycle, adhesion, and cytoskeletal organization. Identified
targets possibly linked to MYC's effects on cell growth include
the nucleolar proteins nucleolin and fibrillarin, as well as the
eukaryotic initiation factor 5A. Among the cell cycle genes identified
as targets, the G1 cyclin D2 and the cyclin-dependent kinase binding
protein CksHs2 were induced whereas the cyclin-dependent kinase
inhibitor p21(Cip1) was repressed. A role for MYC in regulating
cell adhesion and structure is suggested by repression of genes
encoding the extracellular matrix proteins fibronectin and collagen,
and the cytoskeletal protein tropomyosin. A possible mechanism
for MYC-mediated apoptosis was revealed by identification of the
tumor necrosis factor receptor associated protein TRAP1 as a MYC
target. Finally, two immunophilins, peptidyl-prolyl cis-trans
isomerase F and FKBP52, the latter of which plays a role in cell
division in Arabidopsis, were up-regulated by MYC. We also explored
pattern-matching methods as an alternative approach for identifying
MYC target genes. The genes that displayed an expression profile
most similar to endogenous Myc in microarray-based expression
profiling of myeloid differentiation models were highly enriched
for MYC target genes.