PMID- 17363562
OWN - NLM
STAT- MEDLINE
DCOM- 20070419
LR  - 20161124
IS  - 0008-5472 (Print)
IS  - 0008-5472 (Linking)
VI  - 67
IP  - 6
DP  - 2007 Mar 15
TI  - MYCN-directed centrosome amplification requires MDM2-mediated suppression of p53 
      activity in neuroblastoma cells.
PG  - 2448-55
AB  - The MYC family oncogenes cause transformation and tumor progression by corrupting 
      multiple cellular pathways, altering cell cycle progression, apoptosis, and 
      genomic instability. Several recent studies show that MYCC (c-Myc) expression 
      alters DNA repair mechanisms, cell cycle checkpoints, and karyotypic stability, 
      and this is likely partially due to alterations in centrosome replication 
      control. In neuroblastoma cell lines, MYCN (N-Myc) expression induces centrosome 
      amplification in response to ionizing radiation. Centrosomes are cytoplasmic 
      domains that critically regulate cytokinesis, and aberrations in their number or 
      structure are linked to mitotic defects and karyotypic instability. Whereas 
      centrosome replication is linked to p53 and Rb/E2F-mediated cell cycle 
      progression, the mechanisms downstream of MYCN that generate centrosome 
      amplification are incompletely characterized. We hypothesized that MDM2, a direct 
      transcriptional target of MYCN with central inhibitory effects on p53, plays a 
      role in MYC-mediated genomic instability by altering p53 responses to DNA damage, 
      facilitating centrosome amplification. Herein we show that MYCN mediates 
      centrosome amplification in a p53-dependent manner. Accordingly, inhibition of 
      the p53-MDM2 interaction with Nutlin 3A (which activates p53) completely ablates 
      the MYCN-dependent contribution to centrosome amplification after ionizing 
      radiation. We further show that modulating MDM2 expression levels by 
      overexpression or RNA interference-mediated posttranscriptional inhibition 
      dramatically affects centrosome amplification in MYCN-induced cells, indicating 
      that MDM2 is a necessary and sufficient mediator of MYCN-mediated centrosome 
      amplification. Finally, we show a significant correlation between centrosome 
      amplification and MYCN amplification in primary neuroblastoma tumors. These data 
      support the hypothesis that elevated MDM2 levels contribute to MYCN-induced 
      genomic instability through altered regulation of centrosome replication in 
      neuroblastoma.
FAU - Slack, Andrew D
AU  - Slack AD
AD  - Center for Cell and Gene Therapy, Texas Children's Cancer Center, Baylor College 
      of Medicine, Houston, Texas 77030, USA.
FAU - Chen, Zaowen
AU  - Chen Z
FAU - Ludwig, Andrew D
AU  - Ludwig AD
FAU - Hicks, John
AU  - Hicks J
FAU - Shohet, Jason M
AU  - Shohet JM
LA  - eng
GR  - K08-CA90517-02/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
RN  - 0 (MYCN protein, human)
RN  - 0 (N-Myc Proto-Oncogene Protein)
RN  - 0 (Nuclear Proteins)
RN  - 0 (Oncogene Proteins)
RN  - 0 (TP53 protein, human)
RN  - 0 (Tumor Suppressor Protein p53)
RN  - EC 2.3.2.27 (MDM2 protein, human)
RN  - EC 2.3.2.27 (Proto-Oncogene Proteins c-mdm2)
SB  - IM
MH  - Centrosome/*physiology
MH  - DNA Damage
MH  - Genes, p53
MH  - Genomic Instability
MH  - HCT116 Cells
MH  - Humans
MH  - N-Myc Proto-Oncogene Protein
MH  - Neuroblastoma/*genetics/metabolism
MH  - Nuclear Proteins/biosynthesis/*genetics/metabolism
MH  - Oncogene Proteins/biosynthesis/*genetics/metabolism
MH  - Promoter Regions, Genetic
MH  - Proto-Oncogene Proteins c-mdm2/*genetics
MH  - Transcriptional Activation
MH  - Tumor Suppressor Protein p53/*antagonists & inhibitors/biosynthesis/genetics
EDAT- 2007/03/17 09:00
MHDA- 2007/04/20 09:00
CRDT- 2007/03/17 09:00
PHST- 2007/03/17 09:00 [pubmed]
PHST- 2007/04/20 09:00 [medline]
PHST- 2007/03/17 09:00 [entrez]
AID - 67/6/2448 [pii]
AID - 10.1158/0008-5472.CAN-06-1661 [doi]
PST - ppublish
SO  - Cancer Res. 2007 Mar 15;67(6):2448-55. doi: 10.1158/0008-5472.CAN-06-1661.