c-Myc does not prevent glucocorticoid-induced apoptosis of human leukemic lymphoblasts.
Due to their growth arrest- and apoptosis-inducing ability, glucocorticoids (GC) are widely used in the therapy of various lymphoid malignancies. The signal transduction pathways leading to this clinically-relevant form of apoptosis have, however, not been sufficiently elucidated. GC bind to their specific receptor, a ligand-activated transcription factor of the Zn-finger type, that activates or represses transcription of GC-responsive genes. Previous studies in leukemia cells suggested that transcriptional repression of c-myc expression might be the crucial event in GC-induced apoptosis, although in other systems, c-Myc apparently increased the sensitivity to cell-death inducers. To address this controversy, we stably transfected the GC-sensitive human T-ALL cell line CEM-C7H2 with constructs allowing tetracycline-regulated expression of c-Myc. Subsequent analyses of these cell lines showed that overexpression of c-Myc per se had little, if any, effect on cell viability, although it rendered the cells more sensitive to apoptosis induced by low serum, confirming the functionality of the expressed transgene. More importantly, however, when the cells were treated with GC in the presence of exogenous c-Myc, they underwent apoptosis exceeding that in cells treated in the absence of transgenic c-Myc. The data indicate that c-myc downregulation is not critical for induction of cell-death by GC in this system, and support the notion that c-Myc sensitizes cells to apoptosis-inducing agents.
Löffler
M
M
Institute for General and Experimental Pathology, Division of Molecular Pathophysiology, University of Innsbruck, Innsbruck, Austria.
Ausserlechner
M J
MJ
Tonko
M
M
Hartmann
B L
BL
Bernhard
D
D
Geley
S
S
Helmberg
A
A
Kofler
R
R
D017209:Apoptosis / Q000187:drug effects; D016895:Culture Media, Serum-Free; D015536:Down-Regulation; D004318:Doxycycline / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D007938:Leukemia; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D016895:Culture Media, Serum-Free; D005938:Glucocorticoids; D016271:Proto-Oncogene Proteins c-myc; D004318:Doxycycline