Protein arginine methyltransferase 5 is a key regulator of the MYCN oncoprotein in neuroblastoma cells.
Park, JH
Szemes, M
Vieira, GC
Melegh, Z
Malik, S
Heesom, KJ
Von Wallwitz-Freitas, L
Greenhough, A
Brown, KW
Zheng, YG
Catchpoole, D
Deery, MJ
Malik, K
- Publisher:
- Wiley
- Publication Type:
- Journal Article
- Citation:
- Mol Oncol, 2015, 9, (3), pp. 617-627
- Issue Date:
- 2015-03
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Full metadata record
Field | Value | Language |
---|---|---|
dc.contributor.author | Park, JH | |
dc.contributor.author | Szemes, M | |
dc.contributor.author | Vieira, GC | |
dc.contributor.author | Melegh, Z | |
dc.contributor.author | Malik, S | |
dc.contributor.author | Heesom, KJ | |
dc.contributor.author | Von Wallwitz-Freitas, L | |
dc.contributor.author | Greenhough, A | |
dc.contributor.author | Brown, KW | |
dc.contributor.author | Zheng, YG | |
dc.contributor.author | Catchpoole, D | |
dc.contributor.author | Deery, MJ | |
dc.contributor.author | Malik, K | |
dc.date.accessioned | 2022-04-11T04:37:39Z | |
dc.date.available | 2014-10-30 | |
dc.date.available | 2022-04-11T04:37:39Z | |
dc.date.issued | 2015-03 | |
dc.identifier.citation | Mol Oncol, 2015, 9, (3), pp. 617-627 | |
dc.identifier.issn | 1574-7891 | |
dc.identifier.issn | 1878-0261 | |
dc.identifier.uri | http://hdl.handle.net/10453/156059 | |
dc.description.abstract | Approximately half of poor prognosis neuroblastomas (NBs) are characterized by pathognomonic MYCN gene amplification and MYCN over-expression. Here we present data showing that short-interfering RNA mediated depletion of the protein arginine methyltransferase 5 (PRMT5) in cell-lines representative of NBs with MYCN gene amplification leads to greatly impaired growth and apoptosis. Growth suppression is not apparent in the MYCN-negative SH-SY5Y NB cell-line, or in two immortalized human fibroblast cell-lines. Immunoblotting of NB cell-lines shows that high PRMT5 expression is strongly associated with MYCN-amplification (P < 0.004, Mann-Whitney U-test) and immunohistochemical analysis of primary NBs reveals that whilst PRMT5 protein is ubiquitously expressed in the cytoplasm of most cells, MYCN-amplified tumours exhibit pronounced nuclear PRMT5 staining. PRMT5 knockdown in MYCN-overexpressing cells, including the SHEP-21N cell-line with inducible MYCN expression leads to a dramatic decrease in MYCN protein and MYCN-associated cell-death in SHEP-21N cells. Quantitative gene expression analysis and cycloheximide chase experiments suggest that PRMT5 regulates MYCN at a post-transcriptional level. Reciprocal co-immunoprecipitation experiments demonstrated that endogenous PRMT5 and MYCN interact in both SK-N-BE(2)C and NGP cell lines. By using liquid chromatography - tandem mass spectrometry (LC-MS/MS) analysis of immunoprecipitated MYCN protein, we identified several potential sites of arginine dimethylation on the MYCN protein. Together our studies implicate PRMT5 in a novel mode of MYCN post-translational regulation and suggest PRMT5 plays a major role in NB tumorigenesis. Small-molecule inhibitors of PRMT5 may therefore represent a novel therapeutic strategy for neuroblastoma and other cancers driven by the MYCN oncogene. | |
dc.format | Print-Electronic | |
dc.language | eng | |
dc.publisher | Wiley | |
dc.relation.ispartof | Mol Oncol | |
dc.relation.isbasedon | 10.1016/j.molonc.2014.10.015 | |
dc.rights | info:eu-repo/semantics/openAccess | |
dc.subject | 1112 Oncology and Carcinogenesis | |
dc.subject.classification | Oncology & Carcinogenesis | |
dc.subject.mesh | Amino Acid Sequence | |
dc.subject.mesh | Apoptosis | |
dc.subject.mesh | Brain Neoplasms | |
dc.subject.mesh | Cell Cycle | |
dc.subject.mesh | Cell Line, Tumor | |
dc.subject.mesh | Gene Knockdown Techniques | |
dc.subject.mesh | Humans | |
dc.subject.mesh | Molecular Sequence Data | |
dc.subject.mesh | N-Myc Proto-Oncogene Protein | |
dc.subject.mesh | Neuroblastoma | |
dc.subject.mesh | Nuclear Proteins | |
dc.subject.mesh | Oncogene Proteins | |
dc.subject.mesh | Protein Binding | |
dc.subject.mesh | Protein Stability | |
dc.subject.mesh | Protein-Arginine N-Methyltransferases | |
dc.subject.mesh | Cell Line, Tumor | |
dc.subject.mesh | Humans | |
dc.subject.mesh | Neuroblastoma | |
dc.subject.mesh | Brain Neoplasms | |
dc.subject.mesh | Oncogene Proteins | |
dc.subject.mesh | Nuclear Proteins | |
dc.subject.mesh | Cell Cycle | |
dc.subject.mesh | Apoptosis | |
dc.subject.mesh | Amino Acid Sequence | |
dc.subject.mesh | Protein Binding | |
dc.subject.mesh | Molecular Sequence Data | |
dc.subject.mesh | Protein Stability | |
dc.subject.mesh | Gene Knockdown Techniques | |
dc.subject.mesh | Protein-Arginine N-Methyltransferases | |
dc.subject.mesh | N-Myc Proto-Oncogene Protein | |
dc.title | Protein arginine methyltransferase 5 is a key regulator of the MYCN oncoprotein in neuroblastoma cells. | |
dc.type | Journal Article | |
utslib.citation.volume | 9 | |
utslib.location.activity | United States | |
utslib.for | 1112 Oncology and Carcinogenesis | |
pubs.organisational-group | /University of Technology Sydney | |
pubs.organisational-group | /University of Technology Sydney/Faculty of Engineering and Information Technology | |
utslib.copyright.status | open_access | * |
dc.date.updated | 2022-04-11T04:37:35Z | |
pubs.issue | 3 | |
pubs.publication-status | Published | |
pubs.volume | 9 | |
utslib.citation.issue | 3 |
Abstract:
Approximately half of poor prognosis neuroblastomas (NBs) are characterized by pathognomonic MYCN gene amplification and MYCN over-expression. Here we present data showing that short-interfering RNA mediated depletion of the protein arginine methyltransferase 5 (PRMT5) in cell-lines representative of NBs with MYCN gene amplification leads to greatly impaired growth and apoptosis. Growth suppression is not apparent in the MYCN-negative SH-SY5Y NB cell-line, or in two immortalized human fibroblast cell-lines. Immunoblotting of NB cell-lines shows that high PRMT5 expression is strongly associated with MYCN-amplification (P < 0.004, Mann-Whitney U-test) and immunohistochemical analysis of primary NBs reveals that whilst PRMT5 protein is ubiquitously expressed in the cytoplasm of most cells, MYCN-amplified tumours exhibit pronounced nuclear PRMT5 staining. PRMT5 knockdown in MYCN-overexpressing cells, including the SHEP-21N cell-line with inducible MYCN expression leads to a dramatic decrease in MYCN protein and MYCN-associated cell-death in SHEP-21N cells. Quantitative gene expression analysis and cycloheximide chase experiments suggest that PRMT5 regulates MYCN at a post-transcriptional level. Reciprocal co-immunoprecipitation experiments demonstrated that endogenous PRMT5 and MYCN interact in both SK-N-BE(2)C and NGP cell lines. By using liquid chromatography - tandem mass spectrometry (LC-MS/MS) analysis of immunoprecipitated MYCN protein, we identified several potential sites of arginine dimethylation on the MYCN protein. Together our studies implicate PRMT5 in a novel mode of MYCN post-translational regulation and suggest PRMT5 plays a major role in NB tumorigenesis. Small-molecule inhibitors of PRMT5 may therefore represent a novel therapeutic strategy for neuroblastoma and other cancers driven by the MYCN oncogene.
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