mcl-1Is an Immediate-Early Gene Activated by the Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) Signaling Pathway and Is One Component of the GM-CSF Viability Response
mcl-1, abcl-2family member, was originally identified as an early gene induced during differentiation of ML-1 myeloid leukemia cells. In the present study, we demonstrate that Mcl-1 is tightly regulated by the granulocyte-macrophage colony-stimulating factor (GM-CSF) signaling pathway. Upon deprivation of survival factor from TF-1 myeloid progenitor cells, Mcl-1 levels quickly dropped prior to visible detection of apoptosis of these cells. Upon restimulation of these deprived cells with GM-CSF, themcl-1mRNA was immediately induced and its protein product was accordingly resynthesized. Analysis with Ba/F3 cells expressing various truncation mutants of the GM-CSF receptor revealed that the membrane distal region between amino acids 573 and 755 of the receptor β chain was required formcl-1induction. Transient-transfection assays with luciferase reporter genes driven by various regions of themcl-1promoter demonstrated that the upstream sequence between −197 and −69 is responsible for cytokine activation of themcl-1gene. Overexpression ofmcl-1delayed but did not completely prevent apoptosis of cells triggered by cytokine withdrawal. Its down regulation by antisense constructs overcame, at least partially, the survival activity of GM-CSF and induced the apoptosis of TF-1 cells. Taken together, these results suggest thatmcl-1is an immediate-early gene activated by the cytokine receptor signaling pathway and is one component of the GM-CSF viability response.
Chao, J-R; Wang, J-M; Lee, S-F; Peng, H-W; Lin, Y-H; Chou, C-H; Li, J-C; Huang, H-M; Chou, C-K; Kuo, M-L; Yen, JJ-Y; Yang-Yen, H-F
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