Inhibitor of differentiation 4 drives brain tumor-initiating cell genesis through cyclin E and notch signaling
- Hye-Min Jeon1,
- Xun Jin1,
- Joong-Seob Lee1,
- Se-Yeong Oh1,
- Young-Woo Sohn1,
- Hyo-Jung Park1,
- Kyeung Min Joo2,
- Woong-Yang Park3,
- Do-Hyun Nam2,
- Ronald A. DePinho4,
- Lynda Chin4, and
- Hyunggee Kim1,5
- 1 School of Life Sciences and Biotechnology, Korea University, Seoul 136-713, Republic of Korea;
- 2 Department of Neurosurgery, Sungkyunkwan University School of Medicine, Seoul 135-710, Republic of Korea;
- 3 Department of Biochemistry and Molecular Biology, Seoul National University School of Medicine, Seoul 110-799, Republic of Korea;
- 4 Department of Medical Oncology and Center for Applied Cancer Science, Belfer Institute for Innovative Cancer Science, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA
Abstract
Cellular origins and genetic factors governing the genesis and maintenance of glioblastomas (GBM) are not well understood. Here, we report a pathogenetic role of the developmental regulator Id4 (inhibitor of differentiation 4) in GBM. In primary murine Ink4a/Arf−/− astrocytes, and human glioma cells, we provide evidence that enforced Id4 can drive malignant transformation by stimulating increased cyclin E to produce a hyperproliferative profile and by increased Jagged1 expression with Notch1 activation to drive astrocytes into a neural stem-like cell state. Thus, Id4 plays an integral role in the transformation of astrocytes via its combined actions on two-key cell cycle and differentiation regulatory molecules.
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Footnotes
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↵5 Corresponding author.
↵5 E-MAIL hg-kim{at}korea.ac.kr; FAX 82-2-953-0737.
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Supplemental material is available at http://www.genesdev.org.
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Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.1668708.
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- Received March 3, 2008.
- Accepted June 16, 2008.
- Copyright © 2008, Cold Spring Harbor Laboratory Press
