Expression of P27KIP1 is prognostic and independent of MYCN amplification in human neuroblastoma

Bergmann, Eckhard; Wanzel, Michael; Weber, Axel; Shin, Inhee; Christiansen, Holger; Eilers, Martin

doi:10.1002/1097-0215(20010520)95:3<176::aid-ijc1030>3.3.co;2-q

Cited by 10 publications

(19 citation statements)

References 45 publications

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“…Low CDKN1B mRNA expression levels were correlated (P ¼ 1.8 À5 ) with bad prognosis which is in line with previous findings (Supporting Information Fig. S16) (Bergmann et al, 2001). CDKN1B was previously found to be strongly up-regulated during induction of neuronal differentiation and down-regulated by MYCN in a cell line model (Nakamura et al, 2003).…”

Section: No Numeric Dna Aberrations But Frequent Mrna Over-expressionsupporting

confidence: 90%

“…The CDK inhibitors CDKN1A (Cip1/p21) and CDKN1B (Kip1/p27) are extensively studied in neuroblastoma (Kawamata et al, 1996;Poluha et al, 1996;Bergmann et al, 2001;McKenzie et al, 2003;Nakamura et al, 2003). In our tumor panel, the mRNA expression levels of CDKN1A were not up or down-regulated compared with other tumors, and there was no correlation with clinical or genetic characteristics.…”

Section: No Numeric Dna Aberrations But Frequent Mrna Over-expressionmentioning

confidence: 58%

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Copy number defects of G1‐Cell cycle genes in neuroblastoma are frequent and correlate with high expression of E2F target genes and a poor prognosis

Molenaar

Koster

Ebus

et al. 2011

Genes Chromosomes & Cancer

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The tightly controlled network of cell cycle genes consists of a core of cyclin dependent kinases (CDKs) that are activated by periodically expressed cyclins. The activity of the cyclin-CDK complexes is regulated by cyclin dependent kinase inhibitors (CDKIs) and multiple signal transduction routes that converge on the cell cycle. Neuroblastoma are pediatric tumors that belong to the group of small round blue cell tumors, characterized by a fast proliferation. Here, we present high throughput analyses of cell cycle regulating genes in neuroblastoma. We analyzed a series of 82 neuroblastomas by comparative genomic hybridization arrays, single nucleotide polymorphism arrays, and Affymetrix expression arrays and analyzed the datasets in parallel with the R2 bioinformatic tool (http://r2.amc.nl). About 30% of the tumors had genomic amplifications, gains, or losses with shortest regions of overlap that suggested implication of a series of G1 cell cycle regulating genes. CCND1 (cyclin D1) and CDK4 were amplified or gained and the chromosomal regions containing the CDKN2 (INK4) group of CDKIs were frequently deleted. Cluster analysis showed that tumors with genomic aberrations in G1 regulating genes over-expressed E2F target genes, which regulate S and G2/M phase progression. These tumors have a poor prognosis. Our findings suggest that pharmacological inhibition of cell cycle genes might bear therapeutic promises for patients with high risk neuroblastoma.

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Section: No Numeric Dna Aberrations But Frequent Mrna Over-expressionsupporting

confidence: 90%

Section: No Numeric Dna Aberrations But Frequent Mrna Over-expressionmentioning

confidence: 58%

Copy number defects of G1‐Cell cycle genes in neuroblastoma are frequent and correlate with high expression of E2F target genes and a poor prognosis

Molenaar

Koster

Ebus

et al. 2011

Genes Chromosomes & Cancer

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“…Low p27 Kip1 levels correlate with poorer outcomes in human cancers, and high p27 Kip1 levels are good prognostic factors in neuroblastoma (Bergmann et al, 2001). Interestingly, S-and N-cell types usually co-exist within neuroblastoma tumours.…”

Section: Discussionmentioning

confidence: 99%

Targeting Id protein interactions by an engineered HLH domain induces human neuroblastoma cell differentiation

et al. 2009

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Inhibitor of DNA-binding (Id) proteins prevent cell differentiation, promote growth and sustain tumour development. They do so by binding to E proteins and other transcription factors through the helix-loop-helix (HLH) domain, and inhibiting transcription. This makes HLH-mediated Id protein interactions an appealing therapeutic target. We have used the dominant interfering HLH dimerization mutant 13I to model the impact of Id inhibition in two human neuroblastoma cell lines: LA-N-5, similar to immature neuroblasts, and SH-EP, resembling more immature precursor cells. We have validated 13I as an Id inhibitor by showing that it selectively binds to Ids, impairs complex formation with RB, and relieves repression of E protein-activated transcription. Id inactivation by 13I enhances LA-N-5 neural features and causes SH-EP cells to acquire neuronal morphology, express neuronal proteins such as N-CAM and NF-160, proliferate more slowly, and become responsive to retinoic acid. Concomitantly, 13I augments the cell-cycle inhibitor p27 Kip1 and reduces the angiogenic factor vascular endothelial growth factor. These effects are Id specific, being counteracted by Id overexpression. Furthermore, 13I strongly impairs tumorigenic properties in agar colony formation and cell invasion assays. Targeting Id dimerization may therefore be effective for triggering differentiation and restraining neuroblastoma cell tumorigenicity.

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“…Selection for RA-resistant NB cells identified several cell lines that continue to cycle in the presence of RA 39 and have mutations in the RA regulatory region of the N-myc promoter that mediates downregulation of N-myc. Recently, Bergmann et al 16 found that p27 is a good prognostic factor in NB yet this was independent of N-myc amplification. Our model indicates that p27 levels are dependent on the levels of N-myc protein expression.…”

Section: Discussionmentioning

confidence: 99%

“…15 N-myc is a well-known poor prognostic indicator in NB. A recent report indicates that a high level of p27 is a good prognostic factor in NB 16 while decreased p27 is a poor prognostic factor in several malignant tumors. 17 Cell cycle progression in eukaryotes is tightly regulated by cyclins and cyclin-dependent kinases (Cdks).…”

Section: Introductionmentioning

confidence: 99%

Retinoic acid decreases targeting of p27 for degradation via an N-myc-dependent decrease in p27 phosphorylation and an N-myc-independent decrease in Skp2

et al. 2003

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Poor prognosis neuroblastoma (NB) tumors are marked by amplification and overexpression of N-myc. Retinoic acid (RA) decreases N-myc levels and induces cell cycle arrest in vitro and increases event-free survival in advanced stage NB patients. In this study, we investigated the mechanism(s) by which RA regulates cell cycle and how N-myc affects NB cell cycle progression. Constitutive N-myc overexpression stimulates increases in cyclin E-dependent kinase activity and decreases in p27 resulting in increased DNA synthesis.

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Expression of P27KIP1 is prognostic and independent of MYCN amplification in human neuroblastoma

Cited by 10 publications

References 45 publications

Copy number defects of G1‐Cell cycle genes in neuroblastoma are frequent and correlate with high expression of E2F target genes and a poor prognosis

Copy number defects of G1‐Cell cycle genes in neuroblastoma are frequent and correlate with high expression of E2F target genes and a poor prognosis

Targeting Id protein interactions by an engineered HLH domain induces human neuroblastoma cell differentiation

Retinoic acid decreases targeting of p27 for degradation via an N-myc-dependent decrease in p27 phosphorylation and an N-myc-independent decrease in Skp2

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