| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2004: ¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 2003: ¥2,200,000 (Direct Cost: ¥2,200,000)
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| Research Abstract |
We examined the functional diversity of several mutant-p53 derived from human head and neck cancer cell lines. Entire open reading frame of p53 cDNA was subcloned into a mammalian expression vector, and genetic mutations were determined. Then, their intracellular localization, transcriptional activity, and oncogenic function were examined in a human osteosarcoma cell line lacking p53 gene, Saos-2 cells. A mutant-p53 (Glu17Lys,His193Leu) or a truncated-p53 (delta 121) did not activate the reporters containing p53 responsive elements from p21waf1,BAX,MDM2,p53AIP, and PUMA genes. However, a mutant-p53 (Asn30Ser) showed the transcriptional activity on all of the reporters. On the other hand, a mutant-p53 (Asp28lHis) activated the p21waf1 promoter strongly and the MDM2 promoter faintly, but did not activate the BAX promoter. Interestingly, this mutant-p53 prevented Saos-2 cells from undergoing apoptosis after treatment with a DNA damaging agent, adriamycin. This mutant-p53 strongly induced cell cycle arrest but marginally induced apoptosis. Another mutant-p53 (Glu17Lys,His193Leu) also prevented the cells from undergoing apoptosis after DNA damage probably in a transcription-independent manner. These results suggest that some head and neck cancer cell lines contain the oncogenic mutation of p53 gene, and the oncogenic p53 protein prevents cancer cells from undergoing apoptosis after DNA damage.
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