| Budget Amount *help |
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2010: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000)
Fiscal Year 2009: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
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| Research Abstract |
Stress response is an adaptation mechanism to external stimuli of organism, which plays crucial role in determining cell fate such as cell proliferation or death. Thus, immediate early response genes (IEG) sidered as genomic gatekeeper that controls downstream pathway in response to external stress. Among ~40 IEGs, Activating transcription factor (ATF) 3 is a member of the ATF/CREB family of basic-leucine zipper (b-Zip) type transcription factors. Its mRNA level is low or undetectable in most cells, but is greatly induced by a variety of stress signal. This response has dual effects on cell fate, such as cell cycle arrest and apoptosis, or cell survival and proliferation. In the period of this grant, we revealed following biological function of stress response IEG, ATF3. 1) The P1 promoter of ATF3 is conserved between human and mouse and is functional in response to various stimuli, whereas the P1 promoter was dominantly induced by serum and the P2 promoter was more efficiently activat
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ed in response to TGF-β and oncogenic HRAS. In human prostate and Hodgkin Reed-Sternberg cancer cells with elevated expression of ATF3, the P1 promoter was constitutively activated and its chromatin structure was modified into active configuration. The differential usage of alternate promoters of the ATF3 gene at both transcriptional and translational level and the modification of chromatin structure may provide a novel mechanism for expressing ATF3 in determining cell fate during stress response and cancer (Nucleic Acid Res 2009). 2) Novel target gene of ATF3 in UV-irradiated human keratinocyte, p15, was identified. At low dose of UV, ATF3-p15 pathway promotes DNA repair, but cell death pathway was induced at high dose UV via ATF3-Hif2alpha. This provides molecular basis why this stress response gene could control dual cell fate in stress response (Cell Death and Differentiation 2008). 3) ATF3 is negative regulator of Toll-like receptor4 in inflammation. Biological implication of ATF3 in FFA-treated macrophages shows that ATF3 may control inflammatory response in fatty tissue of obesity (Circulation Research 2008). 4) Using genome-wide analysis of DNA damage response genes by combination of expression microarray and ChIP-chip screening of ATF3-binding target genes, we found ATF3 functions an activator of p53 in DNA damage response, but negative regulator of p53 in human cancer such as prostate. 5) In order to further our research of p53-ATF3 axis, we developed ATF3 null mouse and p53/ATF3 double KO mouse. Less
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