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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
7257
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pubmed:dateCreated |
2009-8-13
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pubmed:databankReference |
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pubmed:abstractText |
Acquired uniparental disomy (aUPD) is a common feature of cancer genomes, leading to loss of heterozygosity. aUPD is associated not only with loss-of-function mutations of tumour suppressor genes, but also with gain-of-function mutations of proto-oncogenes. Here we show unique gain-of-function mutations of the C-CBL (also known as CBL) tumour suppressor that are tightly associated with aUPD of the 11q arm in myeloid neoplasms showing myeloproliferative features. The C-CBL proto-oncogene, a cellular homologue of v-Cbl, encodes an E3 ubiquitin ligase and negatively regulates signal transduction of tyrosine kinases. Homozygous C-CBL mutations were found in most 11q-aUPD-positive myeloid malignancies. Although the C-CBL mutations were oncogenic in NIH3T3 cells, c-Cbl was shown to functionally and genetically act as a tumour suppressor. C-CBL mutants did not have E3 ubiquitin ligase activity, but inhibited that of wild-type C-CBL and CBL-B (also known as CBLB), leading to prolonged activation of tyrosine kinases after cytokine stimulation. c-Cbl(-/-) haematopoietic stem/progenitor cells (HSPCs) showed enhanced sensitivity to a variety of cytokines compared to c-Cbl(+/+) HSPCs, and transduction of C-CBL mutants into c-Cbl(-/-) HSPCs further augmented their sensitivities to a broader spectrum of cytokines, including stem-cell factor (SCF, also known as KITLG), thrombopoietin (TPO, also known as THPO), IL3 and FLT3 ligand (FLT3LG), indicating the presence of a gain-of-function that could not be attributed to a simple loss-of-function. The gain-of-function effects of C-CBL mutants on cytokine sensitivity of HSPCs largely disappeared in a c-Cbl(+/+) background or by co-transduction of wild-type C-CBL, which suggests the pathogenic importance of loss of wild-type C-CBL alleles found in most cases of C-CBL-mutated myeloid neoplasms. Our findings provide a new insight into a role of gain-of-function mutations of a tumour suppressor associated with aUPD in the pathogenesis of some myeloid cancer subsets.
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pubmed:grant |
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pubmed:commentsCorrections |
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
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pubmed:status |
MEDLINE
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pubmed:month |
Aug
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pubmed:issn |
1476-4687
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pubmed:author |
pubmed-author:ChibaShigeruS,
pubmed-author:GotohNorikoN,
pubmed-author:HaradaHiroshiH,
pubmed-author:HayashiYasuhideY,
pubmed-author:HiraiHisamaruH,
pubmed-author:HondaHiroakiH,
pubmed-author:KatoMotohiroM,
pubmed-author:KawamataNorihikoN,
pubmed-author:KoefflerH PhillipHP,
pubmed-author:KumanoKeikiK,
pubmed-author:KurokawaMineoM,
pubmed-author:MoriHirakuH,
pubmed-author:NakauchiHiromitsuH,
pubmed-author:NakazakiKumiK,
pubmed-author:NobuyoshiMasaharuM,
pubmed-author:OdaHideakiH,
pubmed-author:OgawaSeishiS,
pubmed-author:OmineMitsuhiroM,
pubmed-author:OnoderaMasafumiM,
pubmed-author:OtsuMakotoM,
pubmed-author:OzawaKeiyaK,
pubmed-author:Sakata-YanagimotoMamikoM,
pubmed-author:SanadaMasashiM,
pubmed-author:ShihLee-YungLY,
pubmed-author:SuzukiTakahiroT,
pubmed-author:TakitaJunkoJ,
pubmed-author:TamuraAzusaA,
pubmed-author:YamagataTetsuyaT,
pubmed-author:YamazakiSatoshiS
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pubmed:issnType |
Electronic
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pubmed:day |
13
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pubmed:volume |
460
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
904-8
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pubmed:meshHeading |
pubmed-meshheading:19620960-Allelic Imbalance,
pubmed-meshheading:19620960-Amino Acid Sequence,
pubmed-meshheading:19620960-Animals,
pubmed-meshheading:19620960-Base Sequence,
pubmed-meshheading:19620960-Chromosomes, Human, Pair 11,
pubmed-meshheading:19620960-Female,
pubmed-meshheading:19620960-Genes, Tumor Suppressor,
pubmed-meshheading:19620960-Humans,
pubmed-meshheading:19620960-Leukemia, Myeloid,
pubmed-meshheading:19620960-Male,
pubmed-meshheading:19620960-Mice,
pubmed-meshheading:19620960-Mice, Knockout,
pubmed-meshheading:19620960-Mice, Nude,
pubmed-meshheading:19620960-Models, Molecular,
pubmed-meshheading:19620960-Molecular Sequence Data,
pubmed-meshheading:19620960-Mutant Proteins,
pubmed-meshheading:19620960-Mutation,
pubmed-meshheading:19620960-NIH 3T3 Cells,
pubmed-meshheading:19620960-Neoplasm Transplantation,
pubmed-meshheading:19620960-Oncogenes,
pubmed-meshheading:19620960-Phosphorylation,
pubmed-meshheading:19620960-Protein Conformation,
pubmed-meshheading:19620960-Proto-Oncogene Proteins c-cbl,
pubmed-meshheading:19620960-Ubiquitination,
pubmed-meshheading:19620960-Uniparental Disomy,
pubmed-meshheading:19620960-ras Proteins
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pubmed:year |
2009
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pubmed:articleTitle |
Gain-of-function of mutated C-CBL tumour suppressor in myeloid neoplasms.
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pubmed:affiliation |
Cancer Genomics Project, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't,
Research Support, N.I.H., Extramural
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