2010年度森基金研究活動報告書
癌細胞におけるサイトカインシグナル伝達経路を用いたアポトーシス誘導に向けて
林謙太郎
政策•メディア研究科 修士課程2年
Mail
to hayaken@sfc.keio.ac.jp
Abstract
The
immune system has highly sophisticated to defend the foreign invaders such as
bacteria and viruses. In this system, Tumor necrosis factor-a(TNF-a) is one of
the key molecules to help kill the cancer or tumors, however, at the certain
time point, TNF-a switch to encourage them to the differentiation or
proliferation for growing tumors. After TNF-a is discovered, it takes around 30
years and much information about TNF-a such as intracellular signaling process,
gene expression following to cellular network and its phenomena are being
restored through wet-bench activities and advanced high throughput
technologies. But comprehensive mechanism of its dynamic cellular processes and
their control such as switching mechanism are still poorly understood. Recent
high-throughput dataset on TNF-a stimulation shows three dynamical patterns
(groups) arising from 180 up-regulated genes in murine embryonic fibroblasts
(MEF). These groups were delineated based on the shape of their temporal
activation profiles. In group 1, the time of peak activation is early (~0.5h)
and decays rapidly. In groups 2 and 3, the peak activation is delayed (~2h and
~12h, respectively) and the decay is very slow. These results were interpreted
to arise due to the rate of instability of mRNA determined by the number of
AU-rich element in the 3'untranslated region (UTR). Recently our group also
developed simple rules using the law of the conservation to shed light on the
various signaling dynamics. Using this approach, we found that the 3 temporal
patterns of gene expressions can be reproduced using the law of conservation
and mass-action equations. Next, in addition to the instability of mRNA, we
show groups 1 and 2 genes are mainly activated by primary signaling with
transcription factors AP-1 and NF-kB with different kinetics and group 3 genes
are induced by secondary signaling such as autocrine stimulations of IL-1 and
IL-6. Here, we compared our model simulation with dynamical experimental data
and suggested the dynamical patterns of gene expression in complex networks can
be represented by simple physical rules.
Poster
presentation
Yamada
D., Hayashi K., Piras V., Tomita M., Tsuchiya M., Selvarajoo K. (2010)
"Signaling Flux Redistribution concept can switch survival to apoptosis in
cancer cells" q-bio conference, New Mexico, USA
現在,本研究によって得られた結果をまとめ,国際論文誌に投稿準備中である.
そのため,結果および考察の図は割愛させて頂いた.
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