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Molecular and Cellular Biology, March 2007, p. 1730-1744, Vol. 27, No. 5
0270-7306/07/$08.00+0     doi:10.1128/MCB.01579-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Reduced Levels of ATF-2 Predispose Mice to Mammary Tumors{dagger} ,{triangledown}

Toshio Maekawa,1 Toshie Shinagawa,1 Yuji Sano,1 Takahiko Sakuma,2 Shintaro Nomura,2 Koichi Nagasaki,3 Yoshio Miki,3 Fumiko Saito-Ohara,4 Johji Inazawa,4 Takashi Kohno,5 Jun Yokota,5 and Shunsuke Ishii1*

Laboratory of Molecular Genetics, RIKEN Tsukuba Institute, 3-1-1 Koyadai, Tsukuba, Ibaraki 305-0074, Japan,1 Department of Pathology, Graduate School of Medicine, Osaka University, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan,2 The Genome Center of the Japanese Foundation for Cancer Research, Kami-ikebukuro, Toshima-ku, Tokyo 170-8455, Japan,3 Department of Molecular Cytogenetics, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan,4 Biology Division, National Cancer Center Research Institute, 1-1 Tsukiji 5-chome, Chuo-ku, Tokyo 104-0045, Japan5

Received 24 August 2006/ Returned for modification 13 October 2006/ Accepted 10 December 2006

Transcription factor ATF-2 is a nuclear target of stress-activated protein kinases, such as p38, which are activated by various extracellular stresses, including UV light. Here, we show that ATF-2 plays a critical role in hypoxia- and high-cell-density-induced apoptosis and the development of mammary tumors. Compared to wild-type cells, Atf-2–/– mouse embryonic fibroblasts (MEFs) were more resistant to hypoxia- and anisomycin-induced apoptosis but remained equally susceptible to other stresses, including UV. Atf-2–/– and Atf-2+/– MEFs could not express a group of genes, such as Gadd45{alpha}, whose overexpression can induce apoptosis, in response to hypoxia. Atf-2–/– MEFs also had a higher saturation density than wild-type cells and expressed lower levels of Maspin, the breast cancer tumor suppressor, which is also known to enhance cellular sensitivity to apoptotic stimuli. Atf-2–/– MEFs underwent a lower degree of apoptosis at high cell density than wild-type cells. Atf-2+/– mice were highly prone to mammary tumors that expressed reduced levels of Gadd45{alpha} and Maspin. The ATF-2 mRNA levels in human breast cancers were lower than those in normal breast tissue. Thus, ATF-2 acts as a tumor susceptibility gene of mammary tumors, at least partly, by activating a group of target genes, including Maspin and Gadd45{alpha}.

* Corresponding author. Mailing address: Laboratory of Molecular Genetics, RIKEN Tsukuba Institute, 3-1-1 Koyadai, Tsukuba, Ibaraki 305-0074, Japan. Phone: 81-29-836-9031. Fax: 81-29-836-9031. E-mail: sishii{at}rtc.riken.jp.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org.

{triangledown} Published ahead of print on 22 December 2006.

Molecular and Cellular Biology, March 2007, p. 1730-1744, Vol. 27, No. 5
0270-7306/07/$08.00+0     doi:10.1128/MCB.01579-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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