| Budget Amount *help |
¥3,700,000 (Direct Cost: ¥3,700,000)
Fiscal Year 2006: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 2005: ¥2,300,000 (Direct Cost: ¥2,300,000)
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| Research Abstract |
In human cancers, missense mutation in the p53 gene, often within the highly conserved DNA binding core domain of the protein, is the most frequent genetic alteration (40-75%). On the other hand, frequency of nonsense or frame shift mutations (truncated protein-producing mutation) in the p53 gene are relatively low, approximately 16% in all of the p53 mutation. Thus, most of the cells with p53 mutation express full-length proteins. Most of the full-length mutant-p53 is believed to inhibit the tumor suppressor function of wild type p53 in a dominant negative fashion. However, it is reported recently that at least certain types of full-length missense mutant-p53 can contribute actively to cancer progression through gain of new oncogenic function. In the present study, we found one interesting mutation of p53 gene (TYS-p53:Asp281His). TYS-p53 did not induce apoptosis, but clearly induced G1 arrest via phosphorylations of serine residue at the specific sites. Hence, TYS-p53 prevented cells from undergoing apoptosis after DNA damage, and might have accelerated the cumulative genetic alterations and malignant progression of the cells resulting from DNA-damaging therapy. We also found another oncogenic mutation of p53 gene, HNt-p53 (Glu17Lys, His193Leu). HNt-p53 might protect against cell death due to DNA damage in a transcription-independent manner, such as an interaction with the mitochondria proteins, or other p53 family proteins, p63 and p73. Pre-therapeutic evaluation of p53 gene is very important for treating patients with head and neck cancer, because the effect of DNA damaging therapy is highly dependent on the status of p53 gene in the tumor cells. This assay system can be utilized to identify the types of abnormality of mutated p53 gene, and the detail information of the mutated p53 gene might provide useful suggestions for the therapeutic strategy.
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