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研究発表を行った学会；
・2008 Global-COE International Summer Retreat.
　２００８年　８月２８日(阿蘇)

タイトル；Transcriptional regulation of a stem cell marker CD133 gene in human tumor cells.
　
発表者；　椨　康一　氏
　　　（熊本大学　発生医学研究センター　転写制御分野）
Abstract；
　CD133 is a glycoprotein containing five transmembrane regions, and originally used as a marker for the isolation of hematopoietic and neural stem cells. Recently, substantial evidence has been accumulating regarding some malignancies that a small population of stem-like cells enriched by CD133 expression is primarily responsible for maintenance of tumors.
To understand the feature of CD133-expressing cells in tumors, we investigated the transcriptional mechanisms of CD133 gene using human colon carcinoma Caco-2 and synovial sarcoma Fuji cell lines (both are CD133-positive) and some glioblastoma cell lines (CD133-negative).
A reporter analysis and electrophoretic mobility shift assays revealed that P5 promoter exhibits the highest activity among five putative promoters (P1 through P5) and identified one ETS binding motif (GGAA) in P5 essential for its optimal activity. Overexpression of dominant-negative forms of Ets2 and Elk1 resulted in significant decrease of P5 activity in Caco-2 cells.
Furthermore, treatment of Caco-2 cells with a specific MEK inhibitor, U0126 diminished the P5 transcription and led to a significant reduction in the numbers of side population (SP) cells, suggesting that MEK/ERK/ETS pathway contributes, at least in part, to maintenance of stem cell character.
Interestingly, treatment with the demethylating agent 5-azacytidine and/or histone deacetylase inhibitor valproic acid dramatically restored the expression of CD133 mRNA in CD133-negative glioblastoma cells. In addition, hypomethylation of CpG sites residing in P1, P2, and P3 promoters were also proven critical for CD133 transcription. These findings provide important insights into the understanding of the feature of CD133-expressing tumor stem cells, and also into the development of eradicative therapies against human malignancies.