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

Abstract

Glucocorticoids (GC) have pronounced effects on metabolism, differentiation, proliferation, and cell survival (1) ⇓ . In certain lymphocytes and lymphocyte-related malignancies, GC inhibit proliferation and induce apoptotic cell death, which has led to their extensive use in the therapy of malignant lymphoproliferative disorders (2) ⇓ . Most of these effects result from regulation of gene expression via the GC receptor (GR), a ligand-activated transcription 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 arrest and apoptosis, we applied DNA chip technology (4 ⇓ , 5) ⇓ to determine gene expression profiles in proliferating and G1/G0-arrested (by conditional expression of the CDK inhibitor p16/INK4a) acute lymphoblastic T cells undergoing GC-induced apoptosis. Of 7074 genes tested, 163 were found to be regulated 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 cells. Analysis of the regulated genes supports the concept that GC-induced apoptosis results from positive GR autoregulation entailing persistent down-regulation of metabolic pathways critical for survival.—Tonko, M., Ausserlechner, M. J., Bernhard, D., Helmberg, A., Kofler, R. Gene expression profiles of proliferating vs. G1/G0 arrested human leukemia cells suggest a mechanism for glucocorticoid-induced apoptosis.