Reference : MDM2 restrains estrogen-mediated AKT activation by promoting TBK1-dependent HPIP degr...
Scientific journals : Article
Life sciences : Biochemistry, biophysics & molecular biology
http://hdl.handle.net/2268/172603
MDM2 restrains estrogen-mediated AKT activation by promoting TBK1-dependent HPIP degradation.
English
Shostak, Kateryna* mailto [Université de Liège - ULiège > Département de pharmacie > Chimie médicale >]
Patrascu, F.* [> >]
Göktuna, Serkan mailto [Université de Liège - ULiège > Département de pharmacie > Chimie médicale >]
Close, Pierre mailto [Université de Liège - ULiège > Département de pharmacie > Chimie médicale >]
Borgs, Laurence mailto [Université de Liège - ULiège > Département des sciences cliniques > Neurologie >]
Nguyen, Laurent mailto [Université de Liège - ULiège > > GIGA - Neurosciences >]
Olivier, Fabrice mailto [Université de Liège - ULiège > > GIGA-R : Services généraux de l'Université >]
Rammal, Ayman []
Brinkhaus, H. []
Bentires-Alj, M. []
Marine, J.-C. []
Chariot, Alain mailto [Université de Liège - ULiège > Département de pharmacie > Chimie médicale >]
* These authors have contributed equally to this work.
May-2014
Cell death and differentiation
5
21
811-24
Yes (verified by ORBi)
International
1350-9047
1476-5403
[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.
http://hdl.handle.net/2268/172603
10.1038/cdd.2014.2

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