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F. Gòdia and M. Fussenegger (Eds.), Animal Cell Technology meets Genomics, 129-131.129YOSHIZAKI K., KATAKURA Y. I. FUJIKI T., TSUNEMATU T., TERUYA K., SHIRAHATA S.HYDROGEN PEROXIDE-INDUCED CELLULAR SENESCENCE IS REGULATED VIA TWO DIFFERENTPATHWAYSLaboratory of Cellular Regulation Technology, Department of Genetic Resources Technology, Graduated School of Bioresource and Bioenvironmental Sciences, Kyushu University, Japan 6-10-1 Hakozaki, Higashi-ku, Fukuoka city, Japan ABSTRACT. Cellular senescence is thought to be an anti-tumor mechanism similar to apoptosis, which suggests that signal mediators participating in the cellular senescence programs might be a novel target for cancer therapy. Until now, several different cellular senescence pathways were reported. One is thetelomere shortening dependent pathway called “replicative senescence”[1]. Another is the telomere shortening independent pathway, which is activated by oncogenic ras, called “premature senescence”[2].Furthermore, we and other researchers have demonstrated that lethal concentration of hydrogen peroxide induces apoptosis, while sublethal concentration of hydrogen peroxide triggers premature senescence in normal cells[3] and A549, human lung adenocarcinoma. In this research, we attempted whether oxidative stress-inducible cellular senescence in A549 cancer cells can function as tumor suppression. r1. INTRODUCTIONNormal somatic cells undergo a limited number of division when cultured in vitrobefore entering an irreversible state of cell cycle arrest known as replicative senescence [1]. This process has been demonstrated to occur also in vivo and isbelieved to play a major role in safeguarding against tumor formation by suppressing the emergence of immortal cells besides to apoptosis. While it has been believed that cell lines lacking cell cycle checkpoint molecules become tumor cells. In fact it has been known that cancer cells are deficient in the pathway at least either tp19 ARF -p53 or p16 INK4b -RB, which are known as cell cycle checkpoint regulators. It has been also reported that A549, human lung adenocarcinoma, is p15 INK4a , p16 INK4bnull cell line. We has been reported that sublethal oxidative stress triggered cellular senescence in A549 cancer cells, suggesting that oxidative stress-inducible cellular senescence might not require the function of p15 INK4a and p16 INK4b . Recently it hasbeen thought that there exist cellular senescence checkpoint mechanisms which is different from cell cycle checkpoint. In the present study, we tried to demonstrate whether A549 cells (p15 -/- , p16 -/- ) undergo cellular senescence in response to© Printed in the Netherlands. Springer. 2005