Medulloblastomas overexpress the p53-inactivating oncogene WIP1/PPM1D.
Medulloblastoma is the most common malignant brain tumor of childhood. Despite numerous advances, clinical challenges range from recurrent and progressive disease to long-term toxicities in survivors. The lack of more effective, less toxic therapies results from our limited understanding of medulloblastoma growth. Although TP53 is the most commonly altered gene in cancers, it is rarely mutated in medulloblastoma. Accumulating evidence, however, indicates that TP53 pathways are disrupted in medulloblastoma. Wild-type p53-induced phosphatase 1 (WIP1 or PPM1D) encodes a negative regulator of p53. WIP1 amplification (17q22-q23) and its overexpression have been reported in diverse cancer types. We examined primary medulloblastoma specimens and cell lines, and detected WIP1 copy gain and amplification prevalent among but not exclusively in the tumors with 17q gain and isochromosome 17q (i17q), which are among the most common cytogenetic lesions in medulloblastoma. WIP1 RNA levels were significantly higher in the tumors with 17q gain or i17q. Immunoblots confirmed significant WIP1 protein in primary tumors, generally higher in those with 17q gain or i17q. Under basal growth conditions and in response to the chemotherapeutic agent, etoposide, WIP1 antagonized p53-mediated apoptosis in medulloblastoma cell lines. These results indicate that medulloblastoma express significant levels of WIP1 that modulate genotoxic responsiveness by negatively regulating p53.
Castellino
Robert C
RC
Department of Pediatrics, Texas Children's Cancer Center, Baylor College of Medicine, 6621 Fannin Street, MC 3-3320, Houston, TX 77030, USA. rccastel@txccc.org
De Bortoli
Massimiliano
M
Lu
Xiongbin
X
Moon
Sung-Hwan
SH
Nguyen
Thuy-Ai
TA
Shepard
Mark A
MA
Rao
Pulivarthi H
PH
Donehower
Lawrence A
LA
Kim
John Y H
JY
D000293:Adolescent; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002648:Child; D002675:Child, Preschool; D002886:Chromosomes, Human, Pair 17; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D049452:Green Fluorescent Proteins / Q000096:biosynthesis; D006801:Humans; D017404:In Situ Hybridization, Fluorescence / Q000379:methods; D020287:In Situ Nick-End Labeling; D007223:Infant; D008297:Male; D008527:Medulloblastoma / Q000235:genetics / Q000378:metabolism*; D010749:Phosphoprotein Phosphatases / Q000235:genetics / Q000378:metabolism*; D000071636:Protein Phosphatase 2C; D012189:Retrospective Studies; D014162:Transfection / Q000379:methods; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D016159:Tumor Suppressor Protein p53; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; C000607458:PPM1D protein, human; D010749:Phosphoprotein Phosphatases; D000071636:Protein Phosphatase 2C