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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
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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