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Mechanism of Regulation of Adipocyte Numbers in Adult Organisms Through Differentiation and Apoptosis Homeostasis
Published on: June 3, 2016
Reduced levels of ATF-2 predispose mice to mammary tumors
Toshio Maekawa1, Toshie Shinagawa, Yuji Sano
1Laboratory of Molecular Genetics, RIKEN Tsukuba Institute, 3-1-1 Koyadai, Tsukuba, Ibaraki 305-0074, Japan.
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.
Insights
The transcription factor ATF-2 is vital for apoptosis and mammary tumor development. ATF-2 deficiency increases resistance to hypoxia-induced apoptosis and promotes mammary tumor formation in mice.
Area of Science:
- Molecular Biology
- Cancer Research
- Cell Biology
Background:
- Activating Transcription Factor 2 (ATF-2) is a nuclear target of stress-activated protein kinases.
- Extracellular stresses, such as UV light, activate protein kinases like p38.
- The role of ATF-2 in stress-induced apoptosis and tumorigenesis requires further elucidation.
Purpose of the Study:
- To investigate the role of ATF-2 in hypoxia- and high-cell-density-induced apoptosis.
- To determine the involvement of ATF-2 in mammary tumor development.
- To identify downstream target genes of ATF-2 in these processes.
Main Methods:
- Utilized Atf-2 knockout (Atf-2(-/-)) and heterozygous (Atf-2(+/-)) mouse embryonic fibroblasts (MEFs) and mice.
- Assessed apoptosis induction under various stress conditions (hypoxia, anisomycin, UV).
- Quantified gene expression of potential ATF-2 targets (Gadd45alpha, Maspin) and analyzed mammary tumor development.
Main Results:
- Atf-2(-/-) MEFs exhibited resistance to hypoxia- and anisomycin-induced apoptosis but not UV-induced apoptosis.
- Hypoxia failed to induce apoptosis-related genes like Gadd45alpha in Atf-2(-/-) MEFs.
- Atf-2(-/-) MEFs showed increased saturation density and reduced Maspin expression, correlating with lower apoptosis at high cell density.
- Atf-2(+/-) mice developed mammary tumors with decreased Gadd45alpha and Maspin levels.
- Lower ATF-2 mRNA levels were observed in human breast cancers compared to normal tissue.
Conclusions:
- ATF-2 plays a critical role in mediating apoptosis in response to specific cellular stresses like hypoxia.
- ATF-2 functions as a tumor susceptibility gene in mammary gland development, partly through regulating target genes such as Maspin and Gadd45alpha.
- Reduced ATF-2 expression is linked to human breast cancer, suggesting its tumor-suppressive role.
