Reduced Levels of ATF-2 Predispose Mice to Mammary Tumors

Overview

Journal Mol Cell Biol

Specialty Cell Biology

Date 2006 Dec 26

PMID 17189429

Citations 42

Authors

Toshio Maekawa

Toshie Shinagawa

Yuji Sano

Takahiko Sakuma

Shintaro Nomura

Koichi Nagasaki

Yoshio Miki

Fumiko Saito-Ohara

Johji Inazawa

Takashi Kohno

Jun Yokota

Shunsuke Ishii

Affiliations

Soon will be listed here.

Abstract

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 Gadd45alpha, 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 Gadd45alpha 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 Gadd45alpha.

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