Inhibitor of differentiation 4 drives brain tumor-initiating cell genesis through cyclin E and notch signaling.
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.
Jeon
Hye-Min
HM
School of Life Sciences and Biotechnology, Korea University, Seoul 136-713, Republic of Korea.
Jin
Xun
X
Lee
Joong-Seob
JS
Oh
Se-Yeong
SY
Sohn
Young-Woo
YW
Park
Hyo-Jung
HJ
Joo
Kyeung Min
KM
Park
Woong-Yang
WY
Nam
Do-Hyun
DH
DePinho
Ronald A
RA
Chin
Lynda
L
Kim
Hyunggee
H
D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000502:physiology*; D002135:Calcium-Binding Proteins / Q000378:metabolism; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D019927:Cyclin E / Q000378:metabolism*; D005909:Glioblastoma / Q000473:pathology; D006801:Humans; D051796:Inhibitor of Differentiation Proteins / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D000072100:Jagged-1 Protein; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000378:metabolism; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism*; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*
D002135:Calcium-Binding Proteins; D019927:Cyclin E; C490128:ID4 protein, human; D051796:Inhibitor of Differentiation Proteins; D036341:Intercellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; C000606274:Jag1 protein, mouse; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; C497761:NOTCH1 protein, human; D012333:RNA, Messenger; D051881:Receptor, Notch1; D000072099:Serrate-Jagged Proteins