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| Status |
Public on Aug 20, 2008 |
| Title |
The undifferentiated phenotype in neuroblastoma depends on Cyclin D1 and CDK4 activity |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by array
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| Summary |
Genomic aberrations of Cyclin D1 (CCND1) and CDK4 in neuroblastoma indicate that dysregulation of the G1 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 over-expression of Cyclin D1 and CDK4 which correlates with histological subgroups and prognosis respectively. Immunohistochemical analysis demonstrated an over-expression of Cyclin D1 in neuroblasts and a low Cyclin D1 expression in all cell types in ganglioneuroma. This suggests an involvement of G1 regulating genes in neuronal differentiation processes which we further evaluated using RNA interference against Cyclin D1 and its kinase partner CDK4 in several neuroblastoma cell lines. This resulted in pRb pathway inhibition as shown by an almost complete disappearance of CDK4 specific pRb phosphorylation; reduction of E2F transcriptional activity and a decrease of Cyclin A protein levels. The Cyclin D1 and CDK4 knock-down resulted in a significant reduction in cell proliferation, a G1 specific cell cycle arrest and moreover an extensive neuronal differentiation. Affymetrix microarray profiling of siRNA treated cells revealed a shift in expression profile towards a neuronal phenotype. Several new potential downstream players are identified. We conclude that neuroblastoma functionally depend on over-expression of G1 regulating genes to maintain their undifferentiated phenotype.
Keywords: Neuroblastoma, CCND1, Cyclin D1, CDK4
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| Overall design |
The Cell line IMR-32 at time point 0 and transiently transfected with siRNA against GFP, Cyclin D1 and CDK4 at time point 48 hours. All experiments are biological triplicates.
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| Contributor(s) |
Molenaar JJ, Ebus ME, Koster J, Sluis Pv, van Noesel CJ, Versteeg R, Caron HN |
| Citation(s) |
18413728 |
| Submission date |
Aug 24, 2007 |
| Last update date |
Mar 25, 2019 |
| Contact name |
Linda Valentijn |
| Organization name |
Academic Medical Centre, University of Amsterdam
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| Department |
Department of Oncogenomics
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| Street address |
P.O. Box 22700
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| City |
Amsterdam |
| ZIP/Postal code |
1100DE |
| Country |
Netherlands |
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| Platforms (1) |
| GPL570 |
[HG-U133_Plus_2] Affymetrix Human Genome U133 Plus 2.0 Array |
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| Samples (13)
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| GSM220189 |
imr-32,gfp siRNA,T=48,2 |
| GSM220191 |
imr-32,cdk4 siRNA,t=48, 2 |
| GSM220199 |
imr-32,t=0,2 |
| GSM220203 |
imr-32,t=0,3 |
| GSM220205 |
imr-32,gfp siRNA,t=48,3 |
| GSM220206 |
imr-32,ccnd1 siRNA,t=48,3 |
| GSM220207 |
imr-32,cdk4 siRNA,t=48,3 |
| GSM220208 |
imr-32,gfp siRNA, t=48, 4 |
| GSM220209 |
imr-32,ccnd1siRNA, t=48, 4 |
| GSM220210 |
imr-32, cdk4 siRNA, t=48, 4 |
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| Relations |
| BioProject |
PRJNA102231 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE8866_RAW.tar |
102.0 Mb |
(http)(custom) |
TAR (of CEL, CHP) |
| Processed data included within Sample table |
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