| Budget Amount *help |
¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 2000: ¥1,000,000 (Direct Cost: ¥1,000,000)
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| Research Abstract |
We analyzed 137 patients with hematological malignancies by the RT-PCR method for expression of the ARF and INK4A genes, both being localized on the same INK4A/ARF locus. Consistent with previous reports regarding the INK4A/ARF locus deletion, we found that patients with nil expression of both genes had malignancies with relatively rapid growth and poor prognosis. Expression levels of the ARF gene, rather than those of the INK4A, had clinical significance : its high expression levels in follicular lymphomas and its low expression levels in diffuse large B-cell lymphoma were associated with poor prognosis. The ARF gene product. p14^<ARF>, inhibits MDM2-associated degradation process of p53 tumor suppressor. Therefore, the significance of the aberrant p53 pathway was strengthened.
Next we tried to clarify the process of emergence of tumor cells with aberrant p53 pathway. We used rat embryo fibroblasts co-transfected with c-myc and activated H-ras oncogenes, which frequently obtain p53 pathway aberrations. These transformants were subjected to r- and K-selection : for r-selection. cells were cultured under an optimum condition and grew exponentially while under K-selection cells were densely passaged and their growth was restrained by overcrowding. Under r-selection, the growth rates became higher and the transformant with a p53 point mutation rapidly deleted the wild-type allele. Under K-selection, tetraploid cells emerged frequently although p53 mutation was not necessarily selected for. These results suggested that emergence of p53 mutantions, frequently observed in human cancers including hematological malignancies, is at least partly due to r-selection.
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