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Mol Cell Biol, August 1998, p. 4883-4898, Vol. 18, No. 8
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

mcl-1 Is 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

Jyh-Rong Chao,1 2 Ju-Ming Wang,1 3 Shern-Fwu Lee,4 Hsien-Wei Peng,1 5 Yi-Hung Lin,1 3 Chiang-Hung Chou,1 Jian-Chiuan Li,1 Huei-Mei Huang,3 4 Chen-Kung Chou,6 Min-Liang Kuo,2 Jeffrey J.-Y. Yen,4 and Hsin-Fang Yang-Yen1 *

Institute of Molecular Biology1 and Institute of Biomedical Sciences,4 Academia Sinica, Institute of Toxicology2 and Institute of Molecular Medicine,5 National Taiwan University Medical School, Graduate Institute of Life Science, National Defense Medical Center,3 and Department of Medical Research, Veterans General Hospital,6 Taipei, Taiwan

Received 4 November 1997/Returned for modification 18 December 1997/Accepted 5 May 1998

mcl-1, a bcl-2 family 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, the mcl-1 mRNA 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 beta  chain was required for mcl-1 induction. Transient-transfection assays with luciferase reporter genes driven by various regions of the mcl-1 promoter demonstrated that the upstream sequence between -197 and -69 is responsible for cytokine activation of the mcl-1 gene. Overexpression of mcl-1 delayed 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 that mcl-1 is an immediate-early gene activated by the cytokine receptor signaling pathway and is one component of the GM-CSF viability response.

* Corresponding author. Mailing address: Institute of Molecular Biology, Academia Sinica, 128 Yen-Jiou Yuan Rd. Sec. 2, NangKang, Taipei 11529, Taiwan, Republic of China. Phone: 886-2-2789-9228. Fax: 886-2-2782-6085. E-mail: IMBYY{at}ccvax.sinica.edu.tw.

Mol Cell Biol, August 1998, p. 4883-4898, Vol. 18, No. 8
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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