Expression analysis with oligonucleotide microarrays reveals that MYC regulates genes involved in growth, cell cycle, signaling, and adhesion

MYC affects normal and neoplastic cell proliferation by altering gene expre ssion, but the precise pathways remain unclear. We used oligonucleotide mic roarray analysis of 6,416 genes and expressed sequence tags to determine ch anges in gene expression caused by activation of c-MYC in primary human fib roblasts. In these experiments, 27 genes were consistently induced, and 9 g enes 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 po ssibly linked to MYC's effects on cell growth include the nucleolar protein s nucleolin and fibrillarin, as well as the eukaryotic initiation factor 5A . Among the cell cycle genes identified as targets, the G1 cyclin D2 and th e cyclin-dependent kinase binding protein CksHs2 were induced whereas the c yclin-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 t he cytoskeletal protein tropomyosin. A possible mechanism far MYC-mediated apoptosis was revealed by identification of the tumor necrosis factor recep tor associated protein TRAP1 as a MYC target. Finally, two immunophilins, p eptidyl-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 ex plored pattern-matching methods as an alternative approach for identifying MYC target genes. The genes that displayed an expression profile most simil ar to endogenous Myc in microarray-based expression profiling of myeloid di fferentiation models were highly enriched for MYC target genes.