Reduced levels of ATF-2 predispose mice to mammary tumors.
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.
Maekawa
Toshio
T
Laboratory of Molecular Genetics, RIKEN Tsukuba Institute, 3-1-1 Koyadai, Tsukuba, Ibaraki 305-0074, Japan.
Shinagawa
Toshie
T
Sano
Yuji
Y
Sakuma
Takahiko
T
Nomura
Shintaro
S
Nagasaki
Koichi
K
Miki
Yoshio
Y
Saito-Ohara
Fumiko
F
Inazawa
Johji
J
Kohno
Takashi
T
Yokota
Jun
J
Ishii
Shunsuke
S
D051698:Activating Transcription Factor 2 / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D000841:Anisomycin / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology; D018797:Cell Cycle Proteins / Q000378:metabolism; D015687:Cell Hypoxia / Q000187:drug effects; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D017930:Genes, Reporter; D016147:Genes, Tumor Suppressor; D020022:Genetic Predisposition to Disease; D006801:Humans; D015674:Mammary Neoplasms, Animal / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000378:metabolism; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000032:analysis; D015843:Serpins / Q000378:metabolism; D014407:Tumor Cells, Cultured; D000097642:GADD45 Proteins
D051698:Activating Transcription Factor 2; D000841:Anisomycin; D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D019384:Nucleic Acid Synthesis Inhibitors; D012333:RNA, Messenger; D015843:Serpins; C497106:Atf2 protein, mouse; C499072:Gadd45a protein, mouse; D000097642:GADD45 Proteins; C085344:SERPIN-B5