Linked Life Data

18520179

Source:http://linkedlifedata.com/resource/pubmed/id/18520179

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
11
pubmed:dateCreated
2008-6-23
pubmed:abstractText
The p53 tumor suppressor is a powerful growth suppressive and pro-apoptotic molecule frequently inactivated in human cancer. Many tumors overproduce its negative regulator MDM2, a specific p53 ubiquitin ligase and transcriptional inhibitor, to disable p53 function. Therefore, p53 activation by inhibiting MDM2 has been proposed as a novel strategy for cancer therapy in tumors expressing wild-type p53. Recently developed small-molecule p53-MDM2 binding inhibitors, the nutlins, selectively activate p53 function and induce cell cycle arrest and apoptosis in cancer cells. By stabilizing p53, nutlins also elevate the cellular level of its transcriptional target MDM2. Here, we present evidence that nutlin-induced MDM2 retains its ubiquitin ligase activity and contributes to the anti-tumor activity of p53-MDM2 binding inhibitors by facilitating the degradation of another p53 inhibitor, MDMX. MDM2 and MDMX levels were analyzed in a panel of 12 randomly selected solid tumor cell lines. In the presence of nutlin-3, MDM2 increased in all and MDMX decreased in most of the cell lines. MDMX was resistant to nutlin-induced degradation in 2/12 cell lines. In these cells, MDMX appears to be a major suppressor of the apoptotic response to p53 activation although this effect was only partially p53-dependent. Doxorubicin facilitated MDMX degradation through DNA damage response pathways and restored their sensitivity to nutlin, suggesting that combination therapy may be an effective way to overcome nutlin resistance in cancers with MDMX aberrations.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
http://linkedlifedata.com/resource/pubmed/chemical/DNA Primers, http://linkedlifedata.com/resource/pubmed/chemical/Doxorubicin, http://linkedlifedata.com/resource/pubmed/chemical/Imidazoles, http://linkedlifedata.com/resource/pubmed/chemical/MDM2 protein, human, http://linkedlifedata.com/resource/pubmed/chemical/MDM4 protein, human, http://linkedlifedata.com/resource/pubmed/chemical/Nuclear Proteins, http://linkedlifedata.com/resource/pubmed/chemical/Piperazines, http://linkedlifedata.com/resource/pubmed/chemical/Proto-Oncogene Proteins, http://linkedlifedata.com/resource/pubmed/chemical/Proto-Oncogene Proteins c-mdm2, http://linkedlifedata.com/resource/pubmed/chemical/RNA, Small Interfering, http://linkedlifedata.com/resource/pubmed/chemical/Tumor Suppressor Protein p53, http://linkedlifedata.com/resource/pubmed/chemical/nutlin 3
pubmed:status
MEDLINE
pubmed:month
Jun
pubmed:issn
1551-4005
pubmed:author
pubmed:issnType
Electronic
pubmed:day
1
pubmed:volume
7
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1604-12
pubmed:dateRevised
2008-10-8
pubmed:meshHeading
pubmed:year
2008
pubmed:articleTitle
Elevated MDM2 boosts the apoptotic activity of p53-MDM2 binding inhibitors by facilitating MDMX degradation.
pubmed:affiliation
Discovery Oncology, Roche Research Center, Hoffmann-La Roche Inc., Nutley, New Jersey 07110, USA.
pubmed:publicationType
Journal Article, Comparative Study