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Cell cycle regulation targets of MYCN identified by gene expression microarrays

Lookup NU author(s): Dr Emma Bell, Emeritus Professor John LunecORCiD, Professor Deborah TweddleORCiD

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Abstract

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 p21WAF1 and hypo RB in p53 wt cell lines.1 Hypothesis: MYCN acts by inhibiting p21 WAF1, and also by p21WAF1 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. ©2007 Landes Bioscience.

Publication metadata

Author(s): Bell, E., Lunec, J., Tweddle, D.

Publication type: Article

Publication status: Published

Journal: Cell Cycle

Year: 2007

Volume: 6

Issue: 10

Pages: 1249-1256

Print publication date: 15/05/2007

Date deposited: 24/11/2010

ISSN (print): 1538-4101

ISSN (electronic): 1551-4005

Publisher: Landes Bioscience

URL: http://www.landesbioscience.com/journals/cc/article/4222/

PubMed id: 17495526

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