Article (Scientific journals)
MDM2 restrains estrogen-mediated AKT activation by promoting TBK1-dependent HPIP degradation.
Shostak, Kateryna; Patrascu, F.; Göktuna, Serkan et al.
2014In Cell Death and Differentiation, 5 (21), p. 811-24
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Abstract :
[en] Restoration of p53 tumor suppressor function through inhibition of its interaction and/or enzymatic activity of its E3 ligase, MDM2, is a promising therapeutic approach to treat cancer. However, because the MDM2 targetome extends beyond p53, MDM2 inhibition may also cause unwanted activation of oncogenic pathways. Accordingly, we identified the microtubule-associated HPIP, a positive regulator of oncogenic AKT signaling, as a novel MDM2 substrate. MDM2-dependent HPIP degradation occurs in breast cancer cells on its phosphorylation by the estrogen-activated kinase TBK1. Importantly, decreasing Mdm2 gene dosage in mouse mammary epithelial cells potentiates estrogen-dependent AKT activation owing to HPIP stabilization. In addition, we identified HPIP as a novel p53 transcriptional target, and pharmacological inhibition of MDM2 causes p53-dependent increase in HPIP transcription and also prevents HPIP degradation by turning off TBK1 activity. Our data indicate that p53 reactivation through MDM2 inhibition may result in ectopic AKT oncogenic activity by maintaining HPIP protein levels.Cell Death and Differentiation advance online publication, 31 January 2014; doi:10.1038/cdd.2014.2.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Shostak, Kateryna  ;  Université de Liège - ULiège > Département de pharmacie > Chimie médicale
Patrascu, F. 
Göktuna, Serkan ;  Université de Liège - ULiège > Département de pharmacie > Chimie médicale
Close, Pierre  ;  Université de Liège - ULiège > Département de pharmacie > Chimie médicale
Borgs, Laurence ;  Université de Liège - ULiège > Département des sciences cliniques > Neurologie
Nguyen, Laurent  ;  Université de Liège - ULiège > GIGA - Neurosciences
Olivier, Fabrice ;  Université de Liège - ULiège > GIGA-R : Services généraux de l'Université
Rammal, Ayman
Brinkhaus, H.
Bentires-Alj, M.
Marine, J.-C.
Chariot, Alain ;  Université de Liège - ULiège > Département de pharmacie > Chimie médicale
 These authors have contributed equally to this work.
Language :
English
Title :
MDM2 restrains estrogen-mediated AKT activation by promoting TBK1-dependent HPIP degradation.
Publication date :
May 2014
Journal title :
Cell Death and Differentiation
ISSN :
1350-9047
eISSN :
1476-5403
Publisher :
Nature Publishing Group, United Kingdom
Volume :
5
Issue :
21
Pages :
811-24
Peer reviewed :
Peer Reviewed verified by ORBi
Available on ORBi :
since 06 October 2014

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