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. 2000 Mar 28;97(7):3260-5.
doi: 10.1073/pnas.97.7.3260.

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

H A Coller  1 , C Grandori, P Tamayo, T Colbert, E S Lander, R N Eisenman, T R Golub
Affiliations

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

H A Coller et al. Proc Natl Acad Sci U S A. .

Abstract

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.

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Figures

Figure 1
Figure 1
Comparison of MYC-ER induction with technical and biological variability. For each gene, the RNA expression level in one sample is given on the x axis and the expression level for the same gene in the other sample is plotted on the y axis. Two-fold changes are indicated. (A) RNA from human leukemia cell line CCRF-CEM (a gift of U. Sherf and J. Weinstein, National Cancer Institute) was subjected to one or two rounds of poly(A) selection, converted into target, and hybridized to oligonucleotide arrays. (B) RNA from WI38 fibroblasts was infected with control vector and then was either induced with OHT or left untreated. (C) RNA from WI38 fibroblasts was MYC-ER infected, OHT-treated or empty vector-infected, OHT-treated.
Figure 2
Figure 2
Venn diagram of the number of genes altered in each of three independent MYC-ER experiments. (A) The criteria for increased gene expression were the following: (i) the gene was called “present” in the MYC-ER + OHT sample; (ii) the ratio of the expression level in the MYC-ER + OHT sample to the expression level in the control + OHT sample was greater than 2; and (iii) the ratio of control + OHT to control was not greater than two. (B) The criteria for decreased gene expression were the following: (i) the gene was called “present” in the control + OHT sample; (ii) the ratio of expression level in the MYC-ER + OHT sample to the expression level in the control + OHT was less than 0.5; and (iii) the ratio of control + OHT to control was not less than 0.5.
Figure 3
Figure 3
Northern blots of target genes. (A) RNA harvested from the indicated MYC-ER samples was used for Northern blots. Also depicted are Northern blot analysis results for RNA samples harvested from fibroblasts infected with a deletion mutant of the MYC-ER fusion protein incapable of transactivating MYC-responsive genes. Ethidium bromide-stained rRNA levels demonstrates similar loading in each lane. Fold inductions comparing MYC-ER infected cells with and without OHT treatment are 2.3 (Northern blot, experiment 1)/2.3 (microarray, experiment 1) and 2.2 (Northern blot, experiment 2)/2.1 (microarray, experiment 2) for FKBP52; 1.8/2.0 and 1.4/2.1 for PPIF; 4.1/3.6 for FABP5. (B) Northern blot analysis results for a fourth MYC-ER experiment are shown for eIF5A and cyclin D2. Fold inductions (MYC-ER+OHT/MYC-ER) are 1.8 (Northern blot)/2.3–3.0 (microarrays) for eIF5A and 3.5/2.2–5.7 for cyclin D2 (C). Northern blot analysis results for p21 showing repression of transcript levels after MYC-ER induction. Max was used as a loading control because its levels are not altered by MYC activation.
Figure 4
Figure 4
Schematic representation of MYC target genes within a cell. Depicted is a selection of the MYC targets identified herein (underlined) along with their subcellular localization. GR, glucocorticoid receptor. See text for further discussion of the functions of the encoded proteins.
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