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Widespread overexpression of epitope-tagged Mdm4 does not accelerate tumor formation in vivo

Sarah De Clercq, Agniezska Gembarska, Geertrui Denecker UGent, Marion Maetens, Michaël Naessens UGent, Katharina Haigh UGent, Jody Haigh UGent and Jean-Christophe Marine UGent (2010) MOLECULAR AND CELLULAR BIOLOGY. 30(22). p.5394-5405
abstract
Mdm2 and Mdm4 are critical negative regulators of p53. A large body of evidence indicates that elevated expression of either Mdm2 or Mdm4 may favor tumor formation by inhibiting p53 tumor suppression function. To explore this possibility in vivo, we generated conditional Mdm2 and Mdm4 transgenic mice. We show that although both transgenes are designed to be expressed ubiquitously and at comparable levels, only the Mdm4 transgenic protein is produced at high levels in vivo. In contrast, exogenous Mdm2 is constitutively degraded in a proteasome-dependent manner, indicating that cells are equipped with efficient mechanisms that prevent Mdm2 accumulation in vivo. Mice that are homozygous for the Mdm4 transgene die during embryogenesis owing to severe vascular maturation defects. Importantly, this lethality is not rescued on a p53-null background, indicating that high levels of Mdm4 impact on a pathway(s) other than p53 that controls vascular and embryonic development. Mice expressing a single copy of the Mdm4 transgene are viable and, surprisingly, are not prone to spontaneous, radiation-induced or E-myc-induced tumor formation. The findings have clear implications for cancer etiology as well as for cancer therapy.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
EMBRYONIC LETHALITY, ONCOPROTEIN MDM2, C-MYC, B-CELL, P53 PATHWAY, DNA-DAMAGE, REGULATE P53, MICE, AMPLIFICATION, ONCOGENE
journal title
MOLECULAR AND CELLULAR BIOLOGY
Mol. Cell. Biol.
volume
30
issue
22
pages
5394 - 5405
Web of Science type
Article
Web of Science id
000283656700012
JCR category
BIOCHEMISTRY & MOLECULAR BIOLOGY
JCR impact factor
6.188 (2010)
JCR rank
41/284 (2010)
JCR quartile
1 (2010)
ISSN
0270-7306
DOI
10.1128/MCB.00330-10
language
English
UGent publication?
yes
classification
A1
copyright statement
I have transferred the copyright for this publication to the publisher
id
1077105
handle
http://hdl.handle.net/1854/LU-1077105
date created
2010-11-19 10:38:17
date last changed
2012-06-26 14:32:11
@article{1077105,
  abstract     = {Mdm2 and Mdm4 are critical negative regulators of p53. A large body of evidence indicates that elevated expression of either Mdm2 or Mdm4 may favor tumor formation by inhibiting p53 tumor suppression function. To explore this possibility in vivo, we generated conditional Mdm2 and Mdm4 transgenic mice. We show that although both transgenes are designed to be expressed ubiquitously and at comparable levels, only the Mdm4 transgenic protein is produced at high levels in vivo. In contrast, exogenous Mdm2 is constitutively degraded in a proteasome-dependent manner, indicating that cells are equipped with efficient mechanisms that prevent Mdm2 accumulation in vivo. Mice that are homozygous for the Mdm4 transgene die during embryogenesis owing to severe vascular maturation defects. Importantly, this lethality is not rescued on a p53-null background, indicating that high levels of Mdm4 impact on a pathway(s) other than p53 that controls vascular and embryonic development. Mice expressing a single copy of the Mdm4 transgene are viable and, surprisingly, are not prone to spontaneous, radiation-induced or E-myc-induced tumor formation. The findings have clear implications for cancer etiology as well as for cancer therapy.},
  author       = {De Clercq, Sarah and Gembarska, Agniezska and Denecker, Geertrui and Maetens, Marion and Naessens, Micha{\"e}l and Haigh, Katharina and Haigh, Jody and Marine, Jean-Christophe},
  issn         = {0270-7306},
  journal      = {MOLECULAR AND CELLULAR BIOLOGY},
  keyword      = {EMBRYONIC LETHALITY,ONCOPROTEIN MDM2,C-MYC,B-CELL,P53 PATHWAY,DNA-DAMAGE,REGULATE P53,MICE,AMPLIFICATION,ONCOGENE},
  language     = {eng},
  number       = {22},
  pages        = {5394--5405},
  title        = {Widespread overexpression of epitope-tagged Mdm4 does not accelerate tumor formation in vivo},
  url          = {http://dx.doi.org/10.1128/MCB.00330-10},
  volume       = {30},
  year         = {2010},
}

Chicago
De Clercq, Sarah, Agniezska Gembarska, Geertrui Denecker, Marion Maetens, Michaël Naessens, Katharina Haigh, Jody Haigh, and Jean-Christophe Marine. 2010. “Widespread Overexpression of Epitope-tagged Mdm4 Does Not Accelerate Tumor Formation in Vivo.” Molecular and Cellular Biology 30 (22): 5394–5405.
APA
De Clercq, Sarah, Gembarska, A., Denecker, G., Maetens, M., Naessens, M., Haigh, K., Haigh, J., et al. (2010). Widespread overexpression of epitope-tagged Mdm4 does not accelerate tumor formation in vivo. MOLECULAR AND CELLULAR BIOLOGY, 30(22), 5394–5405.
Vancouver
1.
De Clercq S, Gembarska A, Denecker G, Maetens M, Naessens M, Haigh K, et al. Widespread overexpression of epitope-tagged Mdm4 does not accelerate tumor formation in vivo. MOLECULAR AND CELLULAR BIOLOGY. 2010;30(22):5394–405.
MLA
De Clercq, Sarah, Agniezska Gembarska, Geertrui Denecker, et al. “Widespread Overexpression of Epitope-tagged Mdm4 Does Not Accelerate Tumor Formation in Vivo.” MOLECULAR AND CELLULAR BIOLOGY 30.22 (2010): 5394–5405. Print.