PubMed:18413728 JSONTXT

{"target":"https://pubannotation.org/docs/sourcedb/PubMed/sourceid/18413728","sourcedb":"PubMed","sourceid":"18413728","source_url":"http://www.ncbi.nlm.nih.gov/pubmed/18413728","text":"Cyclin D1 and CDK4 activity contribute to the undifferentiated phenotype in neuroblastoma.\nGenomic aberrations of Cyclin D1 (CCND1), CDK4, and CDK6 in neuroblastoma indicate that dysregulation of the G(1) entry checkpoint is an important cell cycle aberration in this pediatric tumor. Here, we report that analysis of Affymetrix expression data of primary neuroblastic tumors shows an extensive overexpression of Cyclin D1, which correlates with histologic subgroups. Immunohistochemical analysis showed overexpression of Cyclin D1 in neuroblasts and low Cyclin D1 expression in all cell types in ganglioneuroma. This suggests an involvement of G(1)-regulating genes in neuronal differentiation processes which we further evaluated using RNA interference against Cyclin D1 and its kinase partners CDK4 and CDK6 in several neuroblastoma cell lines. The Cyclin D1 and CDK4 knockdown resulted in pRb pathway inhibition as shown by an almost complete disappearance of CDK4/CDK6-specific pRb phosphorylation, reduction of E2F transcriptional activity, and a decrease of Cyclin A protein levels. Phenotype analysis showed a significant reduction in cell proliferation, a G(1)-specific cell cycle arrest, and, moreover, an extensive neuronal differentiation. Affymetrix microarray profiling of small interfering RNA-treated cells revealed a shift in expression profile toward a neuronal phenotype. Several new potential downstream players are identified. We conclude that neuroblastoma functionally depend on overexpression of G(1)-regulating genes to maintain their undifferentiated phenotype.","tracks":[{"project":"sentences","denotations":[{"id":"TextSentencer_T1","span":{"begin":0,"end":90},"obj":"Sentence"},{"id":"TextSentencer_T2","span":{"begin":91,"end":284},"obj":"Sentence"},{"id":"TextSentencer_T3","span":{"begin":285,"end":467},"obj":"Sentence"},{"id":"TextSentencer_T4","span":{"begin":468,"end":612},"obj":"Sentence"},{"id":"TextSentencer_T5","span":{"begin":613,"end":847},"obj":"Sentence"},{"id":"TextSentencer_T6","span":{"begin":848,"end":1089},"obj":"Sentence"},{"id":"TextSentencer_T7","span":{"begin":1090,"end":1251},"obj":"Sentence"},{"id":"TextSentencer_T8","span":{"begin":1252,"end":1390},"obj":"Sentence"},{"id":"TextSentencer_T9","span":{"begin":1391,"end":1447},"obj":"Sentence"},{"id":"TextSentencer_T10","span":{"begin":1448,"end":1587},"obj":"Sentence"},{"id":"T1","span":{"begin":0,"end":90},"obj":"Sentence"},{"id":"T2","span":{"begin":91,"end":284},"obj":"Sentence"},{"id":"T3","span":{"begin":285,"end":467},"obj":"Sentence"},{"id":"T4","span":{"begin":468,"end":612},"obj":"Sentence"},{"id":"T5","span":{"begin":613,"end":847},"obj":"Sentence"},{"id":"T6","span":{"begin":848,"end":1089},"obj":"Sentence"},{"id":"T7","span":{"begin":1090,"end":1251},"obj":"Sentence"},{"id":"T8","span":{"begin":1252,"end":1390},"obj":"Sentence"},{"id":"T9","span":{"begin":1391,"end":1447},"obj":"Sentence"},{"id":"T10","span":{"begin":1448,"end":1587},"obj":"Sentence"}],"namespaces":[{"prefix":"_base","uri":"http://pubannotation.org/ontology/tao.owl#"}],"attributes":[{"subj":"TextSentencer_T1","pred":"source","obj":"sentences"},{"subj":"TextSentencer_T2","pred":"source","obj":"sentences"},{"subj":"TextSentencer_T3","pred":"source","obj":"sentences"},{"subj":"TextSentencer_T4","pred":"source","obj":"sentences"},{"subj":"TextSentencer_T5","pred":"source","obj":"sentences"},{"subj":"TextSentencer_T6","pred":"source","obj":"sentences"},{"subj":"TextSentencer_T7","pred":"source","obj":"sentences"},{"subj":"TextSentencer_T8","pred":"source","obj":"sentences"},{"subj":"TextSentencer_T9","pred":"source","obj":"sentences"},{"subj":"TextSentencer_T10","pred":"source","obj":"sentences"},{"subj":"T1","pred":"source","obj":"sentences"},{"subj":"T2","pred":"source","obj":"sentences"},{"subj":"T3","pred":"source","obj":"sentences"},{"subj":"T4","pred":"source","obj":"sentences"},{"subj":"T5","pred":"source","obj":"sentences"},{"subj":"T6","pred":"source","obj":"sentences"},{"subj":"T7","pred":"source","obj":"sentences"},{"subj":"T8","pred":"source","obj":"sentences"},{"subj":"T9","pred":"source","obj":"sentences"},{"subj":"T10","pred":"source","obj":"sentences"}]},{"project":"DisGeNET","denotations":[{"id":"T0","span":{"begin":0,"end":9},"obj":"gene:595"},{"id":"T1","span":{"begin":76,"end":89},"obj":"disease:C0700095"},{"id":"T2","span":{"begin":14,"end":18},"obj":"gene:1019"},{"id":"T3","span":{"begin":76,"end":89},"obj":"disease:C0700095"},{"id":"T4","span":{"begin":0,"end":9},"obj":"gene:595"},{"id":"T5","span":{"begin":76,"end":89},"obj":"disease:C0027819"},{"id":"T6","span":{"begin":14,"end":18},"obj":"gene:1019"},{"id":"T7","span":{"begin":76,"end":89},"obj":"disease:C0027819"},{"id":"T8","span":{"begin":125,"end":130},"obj":"gene:595"},{"id":"T9","span":{"begin":268,"end":283},"obj":"disease:C1368871"},{"id":"T10","span":{"begin":125,"end":130},"obj":"gene:595"},{"id":"T11","span":{"begin":151,"end":164},"obj":"disease:C0027819"},{"id":"T12","span":{"begin":125,"end":130},"obj":"gene:595"},{"id":"T13","span":{"begin":151,"end":164},"obj":"disease:C0700095"},{"id":"T14","span":{"begin":114,"end":123},"obj":"gene:595"},{"id":"T15","span":{"begin":268,"end":283},"obj":"disease:C1368871"},{"id":"T16","span":{"begin":133,"end":137},"obj":"gene:1019"},{"id":"T17","span":{"begin":268,"end":283},"obj":"disease:C1368871"},{"id":"T18","span":{"begin":143,"end":147},"obj":"gene:1021"},{"id":"T19","span":{"begin":151,"end":164},"obj":"disease:C0027819"},{"id":"T20","span":{"begin":114,"end":123},"obj":"gene:595"},{"id":"T21","span":{"begin":151,"end":164},"obj":"disease:C0700095"},{"id":"T22","span":{"begin":143,"end":147},"obj":"gene:1021"},{"id":"T23","span":{"begin":268,"end":283},"obj":"disease:C1368871"},{"id":"T24","span":{"begin":114,"end":123},"obj":"gene:595"},{"id":"T25","span":{"begin":151,"end":164},"obj":"disease:C0027819"},{"id":"T26","span":{"begin":143,"end":147},"obj":"gene:1021"},{"id":"T27","span":{"begin":151,"end":164},"obj":"disease:C0700095"},{"id":"T28","span":{"begin":522,"end":531},"obj":"gene:595"},{"id":"T29","span":{"begin":597,"end":611},"obj":"disease:C0017075"},{"id":"T30","span":{"begin":555,"end":564},"obj":"gene:595"},{"id":"T31","span":{"begin":597,"end":611},"obj":"disease:C0017075"},{"id":"T32","span":{"begin":763,"end":772},"obj":"gene:595"},{"id":"T33","span":{"begin":822,"end":835},"obj":"disease:C0700095"},{"id":"T34","span":{"begin":763,"end":772},"obj":"gene:595"},{"id":"T35","span":{"begin":822,"end":835},"obj":"disease:C0027819"},{"id":"T36","span":{"begin":806,"end":810},"obj":"gene:1021"},{"id":"T37","span":{"begin":822,"end":835},"obj":"disease:C0027819"},{"id":"T38","span":{"begin":806,"end":810},"obj":"gene:1021"},{"id":"T39","span":{"begin":822,"end":835},"obj":"disease:C0700095"}],"relations":[{"id":"R1","pred":"associated_with","subj":"T0","obj":"T1"},{"id":"R2","pred":"associated_with","subj":"T2","obj":"T3"},{"id":"R3","pred":"associated_with","subj":"T4","obj":"T5"},{"id":"R4","pred":"associated_with","subj":"T6","obj":"T7"},{"id":"R5","pred":"associated_with","subj":"T8","obj":"T9"},{"id":"R6","pred":"associated_with","subj":"T10","obj":"T11"},{"id":"R7","pred":"associated_with","subj":"T12","obj":"T13"},{"id":"R8","pred":"associated_with","subj":"T14","obj":"T15"},{"id":"R9","pred":"associated_with","subj":"T16","obj":"T17"},{"id":"R10","pred":"associated_with","subj":"T18","obj":"T19"},{"id":"R11","pred":"associated_with","subj":"T20","obj":"T21"},{"id":"R12","pred":"associated_with","subj":"T22","obj":"T23"},{"id":"R13","pred":"associated_with","subj":"T24","obj":"T25"},{"id":"R14","pred":"associated_with","subj":"T26","obj":"T27"},{"id":"R15","pred":"associated_with","subj":"T28","obj":"T29"},{"id":"R16","pred":"associated_with","subj":"T30","obj":"T31"},{"id":"R17","pred":"associated_with","subj":"T32","obj":"T33"},{"id":"R18","pred":"associated_with","subj":"T34","obj":"T35"},{"id":"R19","pred":"associated_with","subj":"T36","obj":"T37"},{"id":"R20","pred":"associated_with","subj":"T38","obj":"T39"}],"namespaces":[{"prefix":"gene","uri":"http://www.ncbi.nlm.nih.gov/gene/"},{"prefix":"disease","uri":"http://purl.bioontology.org/ontology/MEDLINEPLUS/"}],"attributes":[{"subj":"T0","pred":"source","obj":"DisGeNET"},{"subj":"T1","pred":"source","obj":"DisGeNET"},{"subj":"T2","pred":"source","obj":"DisGeNET"},{"subj":"T3","pred":"source","obj":"DisGeNET"},{"subj":"T4","pred":"source","obj":"DisGeNET"},{"subj":"T5","pred":"source","obj":"DisGeNET"},{"subj":"T6","pred":"source","obj":"DisGeNET"},{"subj":"T7","pred":"source","obj":"DisGeNET"},{"subj":"T8","pred":"source","obj":"DisGeNET"},{"subj":"T9","pred":"source","obj":"DisGeNET"},{"subj":"T10","pred":"source","obj":"DisGeNET"},{"subj":"T11","pred":"source","obj":"DisGeNET"},{"subj":"T12","pred":"source","obj":"DisGeNET"},{"subj":"T13","pred":"source","obj":"DisGeNET"},{"subj":"T14","pred":"source","obj":"DisGeNET"},{"subj":"T15","pred":"source","obj":"DisGeNET"},{"subj":"T16","pred":"source","obj":"DisGeNET"},{"subj":"T17","pred":"source","obj":"DisGeNET"},{"subj":"T18","pred":"source","obj":"DisGeNET"},{"subj":"T19","pred":"source","obj":"DisGeNET"},{"subj":"T20","pred":"source","obj":"DisGeNET"},{"subj":"T21","pred":"source","obj":"DisGeNET"},{"subj":"T22","pred":"source","obj":"DisGeNET"},{"subj":"T23","pred":"source","obj":"DisGeNET"},{"subj":"T24","pred":"source","obj":"DisGeNET"},{"subj":"T25","pred":"source","obj":"DisGeNET"},{"subj":"T26","pred":"source","obj":"DisGeNET"},{"subj":"T27","pred":"source","obj":"DisGeNET"},{"subj":"T28","pred":"source","obj":"DisGeNET"},{"subj":"T29","pred":"source","obj":"DisGeNET"},{"subj":"T30","pred":"source","obj":"DisGeNET"},{"subj":"T31","pred":"source","obj":"DisGeNET"},{"subj":"T32","pred":"source","obj":"DisGeNET"},{"subj":"T33","pred":"source","obj":"DisGeNET"},{"subj":"T34","pred":"source","obj":"DisGeNET"},{"subj":"T35","pred":"source","obj":"DisGeNET"},{"subj":"T36","pred":"source","obj":"DisGeNET"},{"subj":"T37","pred":"source","obj":"DisGeNET"},{"subj":"T38","pred":"source","obj":"DisGeNET"},{"subj":"T39","pred":"source","obj":"DisGeNET"}]},{"project":"DisGeNET5_gene_disease","denotations":[{"id":"18413728-0#0#9#gene595","span":{"begin":0,"end":9},"obj":"gene595"},{"id":"18413728-0#14#18#gene1019","span":{"begin":14,"end":18},"obj":"gene1019"},{"id":"18413728-0#76#89#diseaseC0027819","span":{"begin":76,"end":89},"obj":"diseaseC0027819"},{"id":"18413728-0#76#89#diseaseC0700095","span":{"begin":76,"end":89},"obj":"diseaseC0700095"},{"id":"18413728-0#76#89#diseaseC0027819","span":{"begin":76,"end":89},"obj":"diseaseC0027819"},{"id":"18413728-0#76#89#diseaseC0700095","span":{"begin":76,"end":89},"obj":"diseaseC0700095"},{"id":"18413728-3#54#63#gene595","span":{"begin":522,"end":531},"obj":"gene595"},{"id":"18413728-3#87#96#gene595","span":{"begin":555,"end":564},"obj":"gene595"},{"id":"18413728-3#129#143#diseaseC0017075","span":{"begin":597,"end":611},"obj":"diseaseC0017075"},{"id":"18413728-4#193#197#gene1021","span":{"begin":806,"end":810},"obj":"gene1021"},{"id":"18413728-4#209#222#diseaseC0027819","span":{"begin":822,"end":835},"obj":"diseaseC0027819"},{"id":"18413728-4#209#222#diseaseC0700095","span":{"begin":822,"end":835},"obj":"diseaseC0700095"}],"relations":[{"id":"0#9#gene59576#89#diseaseC0027819","pred":"associated_with","subj":"18413728-0#0#9#gene595","obj":"18413728-0#76#89#diseaseC0027819"},{"id":"0#9#gene59576#89#diseaseC0700095","pred":"associated_with","subj":"18413728-0#0#9#gene595","obj":"18413728-0#76#89#diseaseC0700095"},{"id":"0#9#gene59576#89#diseaseC0027819","pred":"associated_with","subj":"18413728-0#0#9#gene595","obj":"18413728-0#76#89#diseaseC0027819"},{"id":"0#9#gene59576#89#diseaseC0700095","pred":"associated_with","subj":"18413728-0#0#9#gene595","obj":"18413728-0#76#89#diseaseC0700095"},{"id":"14#18#gene101976#89#diseaseC0027819","pred":"associated_with","subj":"18413728-0#14#18#gene1019","obj":"18413728-0#76#89#diseaseC0027819"},{"id":"14#18#gene101976#89#diseaseC0700095","pred":"associated_with","subj":"18413728-0#14#18#gene1019","obj":"18413728-0#76#89#diseaseC0700095"},{"id":"14#18#gene101976#89#diseaseC0027819","pred":"associated_with","subj":"18413728-0#14#18#gene1019","obj":"18413728-0#76#89#diseaseC0027819"},{"id":"14#18#gene101976#89#diseaseC0700095","pred":"associated_with","subj":"18413728-0#14#18#gene1019","obj":"18413728-0#76#89#diseaseC0700095"},{"id":"54#63#gene595129#143#diseaseC0017075","pred":"associated_with","subj":"18413728-3#54#63#gene595","obj":"18413728-3#129#143#diseaseC0017075"},{"id":"87#96#gene595129#143#diseaseC0017075","pred":"associated_with","subj":"18413728-3#87#96#gene595","obj":"18413728-3#129#143#diseaseC0017075"},{"id":"193#197#gene1021209#222#diseaseC0027819","pred":"associated_with","subj":"18413728-4#193#197#gene1021","obj":"18413728-4#209#222#diseaseC0027819"},{"id":"193#197#gene1021209#222#diseaseC0700095","pred":"associated_with","subj":"18413728-4#193#197#gene1021","obj":"18413728-4#209#222#diseaseC0700095"}],"attributes":[{"subj":"18413728-0#0#9#gene595","pred":"source","obj":"DisGeNET5_gene_disease"},{"subj":"18413728-0#14#18#gene1019","pred":"source","obj":"DisGeNET5_gene_disease"},{"subj":"18413728-0#76#89#diseaseC0027819","pred":"source","obj":"DisGeNET5_gene_disease"},{"subj":"18413728-0#76#89#diseaseC0700095","pred":"source","obj":"DisGeNET5_gene_disease"},{"subj":"18413728-0#76#89#diseaseC0027819","pred":"source","obj":"DisGeNET5_gene_disease"},{"subj":"18413728-0#76#89#diseaseC0700095","pred":"source","obj":"DisGeNET5_gene_disease"},{"subj":"18413728-3#54#63#gene595","pred":"source","obj":"DisGeNET5_gene_disease"},{"subj":"18413728-3#87#96#gene595","pred":"source","obj":"DisGeNET5_gene_disease"},{"subj":"18413728-3#129#143#diseaseC0017075","pred":"source","obj":"DisGeNET5_gene_disease"},{"subj":"18413728-4#193#197#gene1021","pred":"source","obj":"DisGeNET5_gene_disease"},{"subj":"18413728-4#209#222#diseaseC0027819","pred":"source","obj":"DisGeNET5_gene_disease"},{"subj":"18413728-4#209#222#diseaseC0700095","pred":"source","obj":"DisGeNET5_gene_disease"}]},{"project":"DisGeNet-2017-sample","denotations":[{"id":"T2754","span":{"begin":0,"end":9},"obj":"gene:595"},{"id":"T2755","span":{"begin":76,"end":89},"obj":"disease:C0027819"},{"id":"T2756","span":{"begin":14,"end":18},"obj":"gene:1019"},{"id":"T2757","span":{"begin":806,"end":810},"obj":"gene:1021"},{"id":"T2758","span":{"begin":822,"end":835},"obj":"disease:C0027819"}],"relations":[{"id":"R1","pred":"associated_with","subj":"T2754","obj":"T2755"},{"id":"R2","pred":"associated_with","subj":"T2754","obj":"T2755"},{"id":"R3","pred":"associated_with","subj":"T2756","obj":"T2755"},{"id":"R4","pred":"associated_with","subj":"T2756","obj":"T2755"},{"id":"R5","pred":"associated_with","subj":"T2757","obj":"T2758"},{"id":"R6","pred":"associated_with","subj":"T2757","obj":"T2758"}],"namespaces":[{"prefix":"gene","uri":"http://www.ncbi.nlm.nih.gov/gene/"},{"prefix":"disease","uri":"http://purl.bioontology.org/ontology/MEDLINEPLUS/"}],"attributes":[{"subj":"T2754","pred":"source","obj":"DisGeNet-2017-sample"},{"subj":"T2755","pred":"source","obj":"DisGeNet-2017-sample"},{"subj":"T2756","pred":"source","obj":"DisGeNet-2017-sample"},{"subj":"T2757","pred":"source","obj":"DisGeNet-2017-sample"},{"subj":"T2758","pred":"source","obj":"DisGeNet-2017-sample"}]},{"project":"UBERON-AE","denotations":[{"id":"PD-UBERON-AE-B_T1","span":{"begin":385,"end":394},"obj":"http://purl.obolibrary.org/obo/UBERON_2000106"},{"id":"PD-UBERON-AE-B_T2","span":{"begin":1216,"end":1225},"obj":"http://purl.obolibrary.org/obo/UBERON_2000106"}],"attributes":[{"subj":"PD-UBERON-AE-B_T1","pred":"source","obj":"UBERON-AE"},{"subj":"PD-UBERON-AE-B_T2","pred":"source","obj":"UBERON-AE"}]},{"project":"performance-test","denotations":[{"id":"PD-UBERON-AE-B_T1","span":{"begin":385,"end":394},"obj":"http://purl.obolibrary.org/obo/UBERON_2000106"},{"id":"PD-UBERON-AE-B_T2","span":{"begin":1216,"end":1225},"obj":"http://purl.obolibrary.org/obo/UBERON_2000106"},{"id":"PD-UBERON-AE-B_T3","span":{"begin":670,"end":678},"obj":"http://purl.obolibrary.org/obo/UBERON_2000602"},{"id":"PD-UBERON-AE-B_T4","span":{"begin":1226,"end":1234},"obj":"http://purl.obolibrary.org/obo/UBERON_2000602"},{"id":"PD-UBERON-AE-B_T5","span":{"begin":1371,"end":1379},"obj":"http://purl.obolibrary.org/obo/UBERON_2000602"}],"attributes":[{"subj":"PD-UBERON-AE-B_T1","pred":"source","obj":"performance-test"},{"subj":"PD-UBERON-AE-B_T2","pred":"source","obj":"performance-test"},{"subj":"PD-UBERON-AE-B_T3","pred":"source","obj":"performance-test"},{"subj":"PD-UBERON-AE-B_T4","pred":"source","obj":"performance-test"},{"subj":"PD-UBERON-AE-B_T5","pred":"source","obj":"performance-test"}]}],"config":{"attribute types":[{"pred":"source","value type":"selection","values":[{"id":"sentences","color":"#ec93cc","default":true},{"id":"DisGeNET","color":"#93e6ec"},{"id":"DisGeNET5_gene_disease","color":"#ecd893"},{"id":"DisGeNet-2017-sample","color":"#be93ec"},{"id":"UBERON-AE","color":"#93eca4"},{"id":"performance-test","color":"#ec939b"}]}]}}