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MDM4 is a key therapeutic target in cutaneous melanoma

Agnieszka Gembarska, Flavie Luciani, Clare Fedele, Elisabeth A Russell, Michael Dewaele, Stéphanie Villar, Aleksandra Zwolinska, Sue Haupt, Job de Lange and Dana Yip, et al. (2012) NATURE MEDICINE. 18(8). p.1239-1247
abstract
The inactivation of the p53 tumor suppressor pathway, which often occurs through mutations in TP53 (encoding tumor protein 53) is a common step in human cancer. However, in melanoma-a highly chemotherapy-resistant disease-TP53 mutations are rare, raising the possibility that this cancer uses alternative ways to overcome p53-mediated tumor suppression. Here we show that Mdm4 p53 binding protein homolog (MDM4), a negative regulator of p53, is upregulated in a substantial proportion (similar to 65%) of stage I-IV human melanomas and that melanocyte-specific Mdm4 overexpression enhanced tumorigenesis in a mouse model of melanoma induced by the oncogene Nras. MDM4 promotes the survival of human metastatic melanoma by antagonizing p53 proapoptotic function. Notably, inhibition of the MDM4-p53 interaction restored p53 function in melanoma cells, resulting in increased sensitivity to cytotoxic chemotherapy and to inhibitors of the BRAF (V600E) oncogene. Our results identify MDM4 as a key determinant of impaired p53 function in human melanoma and designate MDM4 as a promising target for antimelanoma combination therapy.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
MALIGNANT-MELANOMA, N-RAS, IN-VIVO, P53 PATHWAY, TUMOR-SUPPRESSOR ACTIVITY, METASTATIC MELANOMA, BREAST-CANCER, STAPLED P53, CELL-DEATH, BRAF
journal title
NATURE MEDICINE
Nat. Med.
volume
18
issue
8
pages
1239 - 1247
Web of Science type
Article
Web of Science id
000307469300030
JCR category
MEDICINE, RESEARCH & EXPERIMENTAL
JCR impact factor
22.864 (2012)
JCR rank
1/119 (2012)
JCR quartile
1 (2012)
ISSN
1078-8956
DOI
10.1038/nm.2863
language
English
UGent publication?
yes
classification
A1
copyright statement
I have transferred the copyright for this publication to the publisher
id
3006936
handle
http://hdl.handle.net/1854/LU-3006936
date created
2012-10-04 17:09:50
date last changed
2012-10-09 14:36:15
@article{3006936,
  abstract     = {The inactivation of the p53 tumor suppressor pathway, which often occurs through mutations in TP53 (encoding tumor protein 53) is a common step in human cancer. However, in melanoma-a highly chemotherapy-resistant disease-TP53 mutations are rare, raising the possibility that this cancer uses alternative ways to overcome p53-mediated tumor suppression. Here we show that Mdm4 p53 binding protein homolog (MDM4), a negative regulator of p53, is upregulated in a substantial proportion (similar to 65\%) of stage I-IV human melanomas and that melanocyte-specific Mdm4 overexpression enhanced tumorigenesis in a mouse model of melanoma induced by the oncogene Nras. MDM4 promotes the survival of human metastatic melanoma by antagonizing p53 proapoptotic function. Notably, inhibition of the MDM4-p53 interaction restored p53 function in melanoma cells, resulting in increased sensitivity to cytotoxic chemotherapy and to inhibitors of the BRAF (V600E) oncogene. Our results identify MDM4 as a key determinant of impaired p53 function in human melanoma and designate MDM4 as a promising target for antimelanoma combination therapy.},
  author       = {Gembarska, Agnieszka and Luciani, Flavie and Fedele, Clare and Russell, Elisabeth A and Dewaele, Michael and Villar, St{\'e}phanie and Zwolinska, Aleksandra and Haupt, Sue and de Lange, Job and Yip, Dana and Goydos, James and Haigh, Jody and Haupt, Ygal and Larue, Lionel and Jochemsen, Aart and Shi, HuBing and Moriceau, Gatien and Lo, Roger S and Ghanem, Ghanem and Shackleton, Mark and Bernal, Federico and Marine, Jean-Christophe},
  issn         = {1078-8956},
  journal      = {NATURE MEDICINE},
  keyword      = {MALIGNANT-MELANOMA,N-RAS,IN-VIVO,P53 PATHWAY,TUMOR-SUPPRESSOR ACTIVITY,METASTATIC MELANOMA,BREAST-CANCER,STAPLED P53,CELL-DEATH,BRAF},
  language     = {eng},
  number       = {8},
  pages        = {1239--1247},
  title        = {MDM4 is a key therapeutic target in cutaneous melanoma},
  url          = {http://dx.doi.org/10.1038/nm.2863},
  volume       = {18},
  year         = {2012},
}

Chicago
Gembarska, Agnieszka, Flavie Luciani, Clare Fedele, Elisabeth A Russell, Michael Dewaele, Stéphanie Villar, Aleksandra Zwolinska, et al. 2012. “MDM4 Is a Key Therapeutic Target in Cutaneous Melanoma.” Nature Medicine 18 (8): 1239–1247.
APA
Gembarska, A., Luciani, F., Fedele, C., Russell, E. A., Dewaele, M., Villar, S., Zwolinska, A., et al. (2012). MDM4 is a key therapeutic target in cutaneous melanoma. NATURE MEDICINE, 18(8), 1239–1247.
Vancouver
1.
Gembarska A, Luciani F, Fedele C, Russell EA, Dewaele M, Villar S, et al. MDM4 is a key therapeutic target in cutaneous melanoma. NATURE MEDICINE. 2012;18(8):1239–47.
MLA
Gembarska, Agnieszka, Flavie Luciani, Clare Fedele, et al. “MDM4 Is a Key Therapeutic Target in Cutaneous Melanoma.” NATURE MEDICINE 18.8 (2012): 1239–1247. Print.