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First published online March 22, 2006
doi: 10.1242/10.1242/jcs.02854

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A novel function of OLIG2 to suppress human glial tumor cell growth via p27^Kip1 transactivation

Kouichi Tabu^1,2,*, Akiko Ohnishi^3,*, Yuji Sunden^1,4, Tadaki Suzuki¹, Masumi Tsuda¹, Shinya Tanaka¹, Toshiyuki Sakai⁵, Kazuo Nagashima¹ and Hirofumi Sawa^2,6,

¹ Laboratory of Molecular and Cellular Pathology, Hokkaido University School of Medicine, Sapporo 060-8638, Japan
² 21st Century COE Program for Zoonosis Control, Hokkaido University School of Medicine, Sapporo 060-8638, Japan
³ Department of Neurosurgery, National Cancer Center, Tokyo 104-0045, Japan
⁴ Laboratory of Comparative Pathology, Hokkaido University School of Veterinary Medicine, Sapporo 060-0818, Japan
⁵ Department of Molecular-Targeting Cancer Prevention, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
⁶ Department of Molecular Pathobiology, Hokkaido University Research Center for Zoonosis Control, Sapporo 060-0818, Japan

Author for correspondence (e-mail: h-sawa{at}czc.hokudai.ac.jp)

Accepted 21 December 2005

The basic helix-loop-helix transcription factor OLIG2 is specifically expressed in cells of the oligodendrocyte lineage. It is also expressed in various tumors originating from glial cells; however, the expression of OLIG2 is rare or weak in glioblastomas, the most malignant gliomas. The role of OLIG2 in glioma remains unclear. To investigate the function of OLIG2 in glial tumor cells, we have established a glioblastoma cell line, U12-1, in which the expression of OLIG2 is induced by the Tet-off system. Induction of OLIG2 resulted in suppression of both the proliferation and anchorage-independent growth of U12-1. It also resulted in an increase in the expression of p27^Kip1. A luciferase assay revealed that the CTF site of the p27^Kip1 gene promoter was essential for OLIG2-dependent activation of p27^Kip1 gene transcription. Electrophoretic mobility shift assays confirmed that a nuclear extract of OLIG2-expressing U12-1 cells contained a protein complex that binds to the CTF site of the p27^Kip1 gene promoter. Furthermore, siRNA against p27^Kip1 rescued the OLIG2-mediated growth and DNA synthesis inhibition of U12-1 cells. These results indicate that OLIG2 suppresses the proliferation of U12-1 and that this effect is mediated by transactivation of the p27^Kip1 gene, and low expression of OLIG2 may be related to the malignant behavior of human glioblastoma.

Key words: OLIG2, p27, Transcription, Glioblastoma, bHLH

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