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1
* Institute of General and Experimental Pathology, Division of Molecular Pathophysiology, University of Innsbruck, A-6020 Innsbruck, Austria; and
Tyrolean Cancer Research Institute, Innsbruck, Innrain 66, A-6020 Innsbruck, Austria
1Correspondence: Tyrolean Cancer Research Institute, Innrain 66, 6020 Innsbruck, Austria. E-mail: Reinhard.Kofler{at}uibk.ac.at
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.
Key Words: glucocorticoid-induced gene regulation • DNA chip expression profiling • acute lymphoid leukemia • pathophysiology
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