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Reduced levels of ATF-2 predispose mice to mammary tumors.

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.
AuthorsToshio Maekawa, Toshie Shinagawa, Yuji Sano, Takahiko Sakuma, Shintaro Nomura, Koichi Nagasaki, Yoshio Miki, Fumiko Saito-Ohara, Johji Inazawa, Takashi Kohno, Jun Yokota, Shunsuke Ishii
JournalMolecular and cellular biology (Mol Cell Biol) Vol. 27 Issue 5 Pg. 1730-44 (Mar 2007) ISSN: 0270-7306 [Print] United States
PMID17189429 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
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
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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