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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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 |
Journal | Molecular and cellular biology
(Mol Cell Biol)
Vol. 27
Issue 5
Pg. 1730-44
(Mar 2007)
ISSN: 0270-7306 [Print] United States |
PMID | 17189429
(Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Activating Transcription Factor 2
- Atf2 protein, mouse
- Cell Cycle Proteins
- Gadd45a protein, mouse
- Nuclear Proteins
- Nucleic Acid Synthesis Inhibitors
- RNA, Messenger
- SERPIN-B5
- Serpins
- Anisomycin
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Topics |
- Activating Transcription Factor 2
(analysis, genetics, metabolism)
- Animals
- Anisomycin
(pharmacology)
- Apoptosis
(drug effects)
- Breast Neoplasms
(genetics, pathology)
- Cell Cycle Proteins
(metabolism)
- Cell Hypoxia
(drug effects)
- Female
- Fibroblasts
(drug effects, metabolism)
- Genes, Reporter
- Genes, Tumor Suppressor
- Genetic Predisposition to Disease
- Humans
- Mammary Neoplasms, Animal
(genetics, metabolism, pathology)
- Mice
- Mice, Inbred BALB C
- Mice, Inbred C57BL
- Mice, Inbred CBA
- Mice, Knockout
- Nuclear Proteins
(metabolism)
- Nucleic Acid Synthesis Inhibitors
(pharmacology)
- Oligonucleotide Array Sequence Analysis
- RNA, Messenger
(analysis)
- Serpins
(metabolism)
- Tumor Cells, Cultured
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