Aberrant p21 regulation in radioresistant primary glioblastoma multiforme cells bearing wild-type p53.
OBJECTIVE
A clearer understanding of the cellular mechanisms involved in the response to ionizing radiation is pivotal to the development of new therapeutic strategies for glioblastoma multiforme (GBM). To gain insight into dynamic functional aspects of cell cycle regulation and the control of apoptosis in GBMs, the authors investigated the molecular changes induced by ionizing radiation in genetically characterized primary GBMs in vitro compared with secondary GBMs, Grades II and III gliomas, and three GBM cell lines.


METHODS
Irradiation of primary GBMs bearing wild-type (wt) p53 invariably fails to invoke the G, checkpoint and apoptosis in vitro. In approximately half of these primary GBMs a defect lies at or above the level of p53 because transcriptional activation of p21 and bax after irradiation does not occur. The failure of a p21 response to irradiation is invariably accompanied by overexpression of p21 mRNA under nonirradiated conditions. In all remaining primary GBMs transcriptional activation of p21 after irradiation does occur, suggesting that a defect downstream from p21 prevents G, arrest.


CONCLUSIONS
These results show that the G, checkpoint and the p53 pathway are dysfunctional in primary GBMs in vitro, despite the presence of an intact p53 gene. The data also suggest that primary GBMs may be divided into two categories on the basis of their p21 response to irradiation.
Kraus
A
A
Department of Neuropathology, University of Marburg, Germany.
Gross
M W
MW
Knuechel
R
R
Münkel
K
K
Neff
F
F
Schlegel
J
J
D000328:Adult; D000368:Aged; D017209:Apoptosis / Q000235:genetics / Q000528:radiation effects; D064007:Ataxia Telangiectasia Mutated Proteins; D001932:Brain Neoplasms; D018797:Cell Cycle Proteins; D002470:Cell Survival / Q000235:genetics / Q000528:radiation effects; D004268:DNA-Binding Proteins; D005260:Female; D016193:G1 Phase / Q000235:genetics / Q000528:radiation effects; D015972:Gene Expression Regulation, Neoplastic / Q000528:radiation effects*; D005909:Glioblastoma; D006801:Humans; D066298:In Vitro Techniques; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008875:Middle Aged; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D011506:Proteins / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D051736:Proto-Oncogene Proteins c-mdm2; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism; D011836:Radiation Tolerance / Q000235:genetics; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D025521:Tumor Suppressor Proteins; D000097642:GADD45 Proteins
D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases; D011506:Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051736:Proto-Oncogene Proteins c-mdm2; D016283:Proto-Oncogene Proteins p21(ras); D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D000097642:GADD45 Proteins; C497206:MDM2 protein, human; C576324:ATM protein, human; C501009:HRAS protein, human