Granulocyte macrophage-colony stimulating factor shows anti-apoptotic activity in neural progenitor cells via JAK/STAT5-Bcl-2 pathway

• Published in: Apoptosis (London) 2011-02, Vol.16 (2), p.127-134
• Main Authors: Choi, Jung Kyoung, Kim, Kil Hwan, Park, Hyeonseon, Park, So Ra, Choi, Byung Hyune
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Apoptosis Regulatory Proteins - genetics; Apoptosis Regulatory Proteins - physiology; Bcl-2; Bcl-xl; Biochemistry; Biomedical and Life Sciences; Biomedicine; Blotting, Western; Cancer Research; Cell Biology; Gene Expression Regulation; GM-CSF; Granulocyte-Macrophage Colony-Stimulating Factor - pharmacology; Granulocyte-Macrophage Colony-Stimulating Factor - physiology; In Situ Nick-End Labeling; JAK/STAT; Janus Kinases - genetics; Janus Kinases - metabolism; MAP Kinase Kinase 1 - metabolism; Mice; Neural progenitor cells (NPCs); Neurons - cytology; Neurons - metabolism; Oncology; Original Paper; Phosphatidylinositol 3-Kinase - metabolism; Proto-Oncogene Proteins c-bcl-2 - genetics; Proto-Oncogene Proteins c-bcl-2 - metabolism; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction - genetics; STAT5 Transcription Factor - genetics; STAT5 Transcription Factor - metabolism; Staurosporine - pharmacology; Stem Cells - cytology; Stem Cells - metabolism; Transducers; Virology
• ISSN: 1360-8185; 1573-675X
• DOI: 10.1007/s10495-010-0552-2

Recently, many studies have shown that granulocyte macrophage-colony stimulating factor (GM-CSF) has anti-apoptotic activity and regulates the expression of anti-apoptotic genes including Bcl-2 family proteins in neuronal cells in vitro and in vivo. This study investigated detailed mechanism of GM-CSF involved in its anti-apoptotic activity and regulation of Bcl-2 expression in neural progenitor cells (NPCs) as a model. NPCs were cultured from the brain of E13 ICR mouse. When NPCs were treated with staurosporine at 1 μM, apoptosis occurred in more than 30% of cells in TUNEL assay. However, apoptosis was significantly inhibited by pre-treatment with GM-CSF at 10 ng/ml. Under the same experimental condition, the expression of both Bcl-2 and Bcl-xl was clearly induced by GM-CSF regardless of staurosporine treatment in RT-PCR and Western blot analyses. GM-CSF was shown to induce the expression of Bcl-2 and Bcl-xl via Janus tyrosine kinase (JAK) but not via phosphatidylinositol 3-kinase (PI3K) or RAS-mitogen activated protein kinase kinase-1 (MEK-1) using specific signal pathway inhibitors. Further analyses showed that the expression of Bcl-2 and Bcl-xl was induced by GM-CSF via signal transducers and activators of transcription 5 (STAT5) and STAT3, respectively. In addition, JAK/STAT5-Bcl-2 pathway but not JAK/STAT3-Bcl-xl pathway was responsible for the anti-apoptotic activity of GM-CSF in NPCs in TUNEL assay. To our knowledge, this study is the first report that shows differential roles of Bcl-2 and Bcl-xl, and their regulation mechanism involved in the anti-apoptotic activity of GM-CSF in NPCs.