MDM2 mediated nuclear exclusion of p53 attenuates etoposide-induced apoptosis in neuroblastoma cells.

2.50
Hdl Handle:
http://hdl.handle.net/10541/84103
Title:
MDM2 mediated nuclear exclusion of p53 attenuates etoposide-induced apoptosis in neuroblastoma cells.
Authors:
Rodriguez-Lopez, A M; Xenaki, D; Eden, Tim O B; Hickman, John A; Chresta, C M
Abstract:
The p53 gene in neuroblastoma tumors (NB) is rarely mutated but the protein accumulates in the cytoplasm. Because p53 can mediate the cytotoxic effects of chemotherapeutic agents, it is important to determine whether accumulation of p53 in the cytoplasm impairs p53 function. Data presented here indicate that hyperactive nuclear export of p53 suppresses etoposide-induced apoptosis but does not prevent growth arrest. We compared p53 function in a pair of NB subclones. Our data show etoposide induces complete trans-location of p53 to the nucleus and activation of apoptosis in the neuroblastic NB cell line SH-SY5Y (N-type), which expresses low levels of MDM2. However, in Schwann cell-like SH-EP1 cells (S-type), which have up to 10-fold higher levels of MDM2, p53 accumulates in the cytoplasm and the cells are extremely resistant to etoposide-induced apoptosis. Notably, when MDM2 expression is inhibited in S-type cells, with a phosphorothioated antisense oligonucleotide (AS5), then p53 accumulates in the nucleus and the SH-EP1 cells undergo apoptosis. Surprisingly, induction of p21 and G1-arrest are not attenuated in S-type cells, despite the predominantly cytoplasmic location of p53. Whereas, G1-arrest is attenuated in the SH-SY5Y cells, which have high levels of nuclear p53. Taken together, these findings suggest attenuation of G1-arrest is related to the differentiation status of neuroblastomas and occurs downstream of p53 nuclear accumulation. These results demonstrate for the first time that hyperactive nuclear export of p53 attenuates chemotherapy-induced apoptosis in NB cells, and our findings suggest that inhibitors of MDM2 may enhance the therapeutic efficacy of etoposide by promoting apoptosis rather than trans-differentiation.
Affiliation:
Department of Biochemistry, University of Oxford, South Parks Road, Oxford, U.K.
Citation:
MDM2 mediated nuclear exclusion of p53 attenuates etoposide-induced apoptosis in neuroblastoma cells. 2001, 59 (1):135-43 Mol. Pharmacol.
Journal:
Molecular Pharmacology
Issue Date:
Jan-2001
URI:
http://hdl.handle.net/10541/84103
PubMed ID:
11125034
Type:
Article
Language:
en
ISSN:
0026-895X
Appears in Collections:
All Christie Publications

Full metadata record

DC FieldValue Language
dc.contributor.authorRodriguez-Lopez, A Men
dc.contributor.authorXenaki, Den
dc.contributor.authorEden, Tim O Ben
dc.contributor.authorHickman, John Aen
dc.contributor.authorChresta, C Men
dc.date.accessioned2009-10-12T17:19:56Z-
dc.date.available2009-10-12T17:19:56Z-
dc.date.issued2001-01-
dc.identifier.citationMDM2 mediated nuclear exclusion of p53 attenuates etoposide-induced apoptosis in neuroblastoma cells. 2001, 59 (1):135-43 Mol. Pharmacol.en
dc.identifier.issn0026-895X-
dc.identifier.pmid11125034-
dc.identifier.urihttp://hdl.handle.net/10541/84103-
dc.description.abstractThe p53 gene in neuroblastoma tumors (NB) is rarely mutated but the protein accumulates in the cytoplasm. Because p53 can mediate the cytotoxic effects of chemotherapeutic agents, it is important to determine whether accumulation of p53 in the cytoplasm impairs p53 function. Data presented here indicate that hyperactive nuclear export of p53 suppresses etoposide-induced apoptosis but does not prevent growth arrest. We compared p53 function in a pair of NB subclones. Our data show etoposide induces complete trans-location of p53 to the nucleus and activation of apoptosis in the neuroblastic NB cell line SH-SY5Y (N-type), which expresses low levels of MDM2. However, in Schwann cell-like SH-EP1 cells (S-type), which have up to 10-fold higher levels of MDM2, p53 accumulates in the cytoplasm and the cells are extremely resistant to etoposide-induced apoptosis. Notably, when MDM2 expression is inhibited in S-type cells, with a phosphorothioated antisense oligonucleotide (AS5), then p53 accumulates in the nucleus and the SH-EP1 cells undergo apoptosis. Surprisingly, induction of p21 and G1-arrest are not attenuated in S-type cells, despite the predominantly cytoplasmic location of p53. Whereas, G1-arrest is attenuated in the SH-SY5Y cells, which have high levels of nuclear p53. Taken together, these findings suggest attenuation of G1-arrest is related to the differentiation status of neuroblastomas and occurs downstream of p53 nuclear accumulation. These results demonstrate for the first time that hyperactive nuclear export of p53 attenuates chemotherapy-induced apoptosis in NB cells, and our findings suggest that inhibitors of MDM2 may enhance the therapeutic efficacy of etoposide by promoting apoptosis rather than trans-differentiation.en
dc.language.isoenen
dc.subjectCultured Tumour Cellsen
dc.subjectTumour Suppressor Protein p53en
dc.subject.meshAntineoplastic Agents, Phytogenic-
dc.subject.meshApoptosis-
dc.subject.meshCell Nucleus-
dc.subject.meshDNA Damage-
dc.subject.meshEtoposide-
dc.subject.meshGene Silencing-
dc.subject.meshHumans-
dc.subject.meshNeuroblastoma-
dc.subject.meshNuclear Proteins-
dc.subject.meshProto-Oncogene Proteins-
dc.subject.meshProto-Oncogene Proteins c-mdm2-
dc.subject.meshSubcellular Fractions-
dc.subject.meshTranscriptional Activation-
dc.subject.meshTumor Cells, Cultured-
dc.subject.meshTumor Suppressor Protein p53-
dc.titleMDM2 mediated nuclear exclusion of p53 attenuates etoposide-induced apoptosis in neuroblastoma cells.en
dc.typeArticleen
dc.contributor.departmentDepartment of Biochemistry, University of Oxford, South Parks Road, Oxford, U.K.en
dc.identifier.journalMolecular Pharmacologyen
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