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Involvement of PLAGL2 in activation of iron deficient- and hypoxia-induced gene expression in mouse cell lines

Oncogene volume 20, pages 4718–4727 (2001)Cite this article

Abstract

We searched iron-deficient inducible cDNA, using subtraction cloning and mRNA from desferrioxamine-treated mouse macrophage Raw264.7 cells. We identified a pleomorphic adenoma gene like 2 (PLAGL2), one of PLAG superfamily proteins exhibiting antiproliferative properties on tumor cells. Mouse PLAGL2 consists of 496 amino acids with seven C2H2 zinc-fingers. PLAGL2 mRNA was induced in RAW264.7 cells, mouse erythroleukemia cells and Balb/c 3T3 cells when they were treated with desferrioxamine. Hypoxia also increased PLAGL2 mRNA. Expression of PLAGL2 in COS-7 cells led to nuclear localization. PLAGL2 had potential binding ability to GC-rich oligonucleotide and activated transcription of a gene with the binding sequence in transient reporter assay, a finding consistent with a case seen in a PLAGL2 homolog, ZAC-1. Transient co-transfection of PLAGL2 or ZAC1 cDNA and a reporter containing a lactate dehydrogenase A (LDHA) promoter carrying the hypoxia inducible factor-1 responsive element led to an increase in the basal transcription in Balb/c 3T3 and HepG2 cells. Activation in transcription from the LDHA promoter increased by desferrioxamine treatment or hypoxia was further enhanced when PLAGL2 was expressed. We propose that PLAGL2 is involved in the cell cycle arrest and apoptosis of tumor cells by regulating iron depletion- or hypoxia-inducible gene expression.

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Abbreviations

IRE:

iron-responsive element

IRF:

iron regulatory factors

HIF-1:

hypoxia inducible factor-1

LDHA:

lactate dehydrogenase A

PLAG:

pleomorphic adenomas gene

PLAGL1/2:

PLAG like 1/2

FCS:

fetal calf serum

DMEM:

Dulbecco's modified Eagle medium

MEL:

mouse erythroleukemia

DTT:

dithiothreitol

PMSF:

phenylmethylsulfonyl fluoride

TK:

thymidine kinase

GST:

glutathione S-transferase, PCR, polymerase chain reaction

kb:

kilobase pair(s)

kDa:

kilodalton(s)

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Acknowledgements

We thank K Yasaka for excellent technical assistance and M Ohara for comments. This study was supported in part by grants from Ministry of Education, Science, Sports and Culture of Japan.

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Authors and Affiliations

  1. Department of Hygiene, Kansai Medical University, Osaka, 570-8506, Japan

    Takako Furukawa & Rikio Tokunaga

  2. Department of Microbiology, Kansai Medical University, Osaka, 570-8506, Japan

    Jun-ichi Fujisawa

  3. First Department of Pathology, Kansai Medical University, Osaka, 570-8506, Japan

    Yasushi Adachi & Susumu Ikehara

  4. Department of Life Science, Kyoto University, 606-01, Japan

    Taiho Kambe, Yuko Yamaguchi-Iwai & Ryuzo Sasaki

  5. Institute for Medicinal Resources, Faculty of Pharmaceutical Sciences, University of Tokushima, Tokushima, 770-8505, Japan

    Jun Kuwahara

  6. Department of Biotechnology, Kyoto Institute of Technology, Kyoto, 606-8585, Japan

    Shigeru Taketani

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  1. Takako Furukawa
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  2. Yasushi Adachi
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Correspondence to Takako Furukawa.

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Furukawa, T., Adachi, Y., Fujisawa, Ji. et al. Involvement of PLAGL2 in activation of iron deficient- and hypoxia-induced gene expression in mouse cell lines. Oncogene 20, 4718–4727 (2001). https://doi.org/10.1038/sj.onc.1204647

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