The transforming activities of MDM2 in cultured neonatal rat astrocytes.
Although the molecular events regulating the pathogenesis of malignant astrocytomas remains unclear, the inactivation of tumor suppressor genes may be a key factor. The inactivation of p53 by mutation or deletion, however, is not the only obligatory step in astrocytoma genesis. The MDM2 protein has been shown to bind to and downmodulate p53 function, and to have oncogenic capacity. The MDM2 gene is also amplified and overexpressed in a subset of malignant astrocytomas without p53 mutation. Here we show that overexpression of MDM2 promoted the DNA synthesis of cultured neonatal rat astrocytes (RNB cells), abrogated the transcriptional activity of wild-type p53, conferred invasive activity, and subsequently induced the transformation from astrocytes to high-grade astrocytomas. Intriguingly, MDM2 enhanced the expression of angiogenic mitogens; basic fibroblast growth factor (bFGF) and platelet-derived growth factor (PDGF) in RNB cells. These results indicate that MDM2 may play an important role in the progression of astrocytomas, by not only conferring invasive activity but also stimulating the expression of angiogenic growth factors.
Kondo
S
S
Department of Neurosurgery/S80, Brain Tumor Center/Cancer Center, The Cleveland Clinic Foundation, Ohio 44195, USA.
Morimura
T
T
Barnett
G H
GH
Kondo
Y
Y
Peterson
J W
JW
Kaakaji
R
R
Takeuchi
J
J
Toms
S A
SA
Liu
J
J
Werbel
B
B
Barna
B P
BP
D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism*; D002448:Cell Adhesion; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins; D010982:Platelet-Derived Growth Factor / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2; D051381:Rats
D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D010982:Platelet-Derived Growth Factor; D011518:Proto-Oncogene Proteins; D016222:Fibroblast Growth Factor 2; C497208:Mdm2 protein, rat; D051736:Proto-Oncogene Proteins c-mdm2