Gene expression profiles of proliferating vs. G1/G0 arrested human leukemia cells suggest a mechanism for glucocorticoid-induced apoptosis

Glucocorticoids (GC) have pronounced effects on metabolism, differentiation , proliferation, and cell survival (1). In certain lymphocytes and lymphocy te-related malignancies, GC inhibit proliferation and induce apoptotic cell . death, which has led to their extensive use in the therapy of malignant l ymphoproliferative disorders (2). Most of these effects result from regulat ion of gene expression via the GC receptor (GI), a ligand-activated transcr iption factor (3). Although hundreds of genes are regulated by GC (1), how certain biological GC effects relate to individual gene regulation remains enigmatic. To address this question with respect to GC-induced cell cycle a rrest and apoptosis, we applied DNA chip technology (4, 5) to determine gen e expression profiles in proliferating and G1/G0-arrested (by conditional e xpression of the CDK inhibitor p16/INK4a) acute lymphoblastic T cells under going GC-induced apoptosis. Of 7074 genes tested, 163 were found to be regu lated by dexamethasone in the first 8 h in proliferating cells and 66 genes in G1/G0-arrested cells. An almost nonoverlapping set of genes (i.e., only eight genes) was coordinately regulated in proliferating and arrested cell s. Analysis of the regulated genes supports the concept that GC-induced apo ptosis results from positive GR autoregulation entailing persistent down-re gulation of metabolic pathways critical for survival.-Tonko, Ml, Ausserlech ner, M. J., Bernhard, D., Helmberg, A., Kofler, R. Gene expression profiles of proliferating vs. G1/G0 arrested human leukemia cells suggest a mechani sm for glucocorticoid-induced apoptosis.