Cell cycle regulation targets of MYCN identified by gene expression microarrays
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Bell, Emma
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Univ Newcastle Upon Tyne, No Inst Canc Res, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, EnglandUniv Newcastle Upon Tyne, No Inst Canc Res, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England
Bell, Emma
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Lunec, John
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Tweddle, Deborah A.
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Univ Newcastle Upon Tyne, No Inst Canc Res, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, EnglandUniv Newcastle Upon Tyne, No Inst Canc Res, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England
Tweddle, Deborah A.
[1
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[1] Univ Newcastle Upon Tyne, No Inst Canc Res, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England
Background: We have previously shown that MYCN knockdown causes a G(1) arrest in MYCN amplified (MNA), p53 wild type (wt) and p53 mutant MNA neuroblastoma cell lines, with increases in p21(WAF1) and hypo RB in p53 wt cell lines. 1 Hypothesis: MYCN acts by inhibiting p21(WAF1), and also by p21(WAF1) independent mechanisms to override the G1 checkpoint in exponentially growing cells. Methods: Genes potentially regulated by MYCN were identified using gene expression microarrays in p53 wt MNA IMR - 32 and p53 mutant MNA SKNBE(2c) neuroblastoma cell lines treated with MYCN or scrambled siRNA. Results were validated using qRT - PCR and confirmed using the regulatable MYCN expression system (SHEP Tet21N). Results: MYCN knockdown altered the expression of several cell cycle related genes. SKP2 was down regulated in both cell lines, and up regulated in MYCN+Tet21N cells. Expression of the WNT antagonist DKK3 increased in both cell lines and decreased in MYCN+ Tet21N cells. Expression of CDKN1C (p57(cip2)) and TP53INP1 also increased after MYCN knockdown. Conclusions: MYCN may override the G1 checkpoint through down - regulation of SKP2 and TP53INP1 resulting in reduced p21WAF1 expression in p53 wt cell lines, and in addition may act through the WNT signaling pathway in a p53 independent manner.