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J. Biol. Chem., Vol. 277, Issue 18, 15851-15858, May 3, 2002
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From the Pleomorphic adenomas gene-like 2 (PLAGL2)
protein containing seven C2H2 zinc finger
motifs exhibits DNA binding and transcriptional activation activity and
is expressed in response to hypoxia or iron deficiency. To identify the
target genes of PLAGL2, we transfected mouse PLAGL2 cDNA into
Balb/c3T3 fibroblasts and neuroblastoma Neuro2a cells. Both
cells were induced to undergo apoptosis by the expression of PLAGL2 as
judged by assays of TUNEL (terminal deoxynucleotidyltransferase-mediated dUTP nick end-labeling), DNA fragmentation, propidium iodide staining, and the binding of
annexin V to the cell surface. The treatment of the cells with an iron
chelator, desferrioxamine, resulted in the induction of apoptosis with
a concomitant accumulation of PLAGL2 in the nucleus. The expression of
PLAGL2 in Balb/c3T3 cells led to the mRNA expression of a
proapoptotic factor, Nip3, which can dimerize with Bcl-2. Nip3 mRNA
was also induced in desferrioxamine-treated cells. Furthermore, the
Nip3 promoter containing a hypoxia-responsive element was activated by
PLAGL2, independent of hypoxia-inducible factor-1 (HIF-1). The
transfection of antisense oligonucleotide to mouse Nip3 mRNA into
PLAGL2-expressing cells led to a decrease in apoptotic cells compared
with sense oligonucleotide-transfected cells. Despite the activation of
DNA-HIF-1 binding activity under hypoxic conditions, neither an
accumulation of HIF-1
A Zinc-finger Protein, PLAGL2, Induces the Expression of a
Proapoptotic Protein Nip3, Leading to Cellular Apoptosis*
,
Department of Biotechnology, Kyoto Institute
of Technology, Sakyo-ku, Kyoto 606-8585, Japan, the
§ Biomedical Imaging Research Center, Fukui Medical
University, Matsuoka-cho, Fukui 910-1193, Japan, and the
¶ First Department of Pathology, Kansai Medical University,
Moriguchi, Osaka 570-8506, Japan
nor the activation of HIF-1 was observed
following the expression of PLAGL2. These results indicate that PLAGL2
is located downstream of HIF-1 and suggest that PLAGL2 functions as a
tumor suppressor in association with HIF-1.
*
This study was supported in part by grants from the Ministry
of Education, Science, Sports and Culture of Japan and the Yamanouchi Foundation for Research on Metabolic Disorders.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed. Tel.:
81-75-724-7789; Fax: 81-75-724-7760; E-mail:
taketani@ipc.kit.ac.jp.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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