The p53 pathway and its inactivation in neuroblastoma.
Early studies of p53 in neuroblastoma reported infrequent mutations in tumours and cell lines. Cytoplasmic sequestration was later proposed as an alternative mechanism of inactivation, but many studies have since reported an intact p53 pathway in neuroblastoma cell lines, as detected by nuclear p53 accumulation after DNA damage, intact DNA binding, transcriptional activation of target genes and the induction of apoptosis. In some MYCN amplified cell lines however, an irradiation induced G(1) arrest does not occur, despite the presence of normal p53. Neuroblastoma usually responds to chemotherapy but frequently relapses, and there is evidence from tumours, and cell lines that p53 inactivation via mutation or MDM2 amplification occurs at relapse and is sometimes associated with multidrug resistance. If p53 inactivation occurs frequently in relapsed tumours it may be appropriate to include p53 independent therapies in the initial management of high-risk neuroblastoma.
Tweddle
Deborah A
DA
Cancer Research Unit, The Medical School, University of Newcastle, Newcastle-upon-Tyne NE2 4HH, UK. d.a.tweddle@newcastle.ac.uk
Pearson
Andrew D J
AD
Haber
Michelle
M
Norris
Murray D
MD
Xue
Chengyuan
C
Flemming
Claudia
C
Lunec
John
J
D017209:Apoptosis; D004249:DNA Damage; D005784:Gene Amplification; D016259:Genes, myc; D006801:Humans; D009154:Mutation; D009447:Neuroblastoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2