MDM2 restrains estrogen-mediated AKT activation by promoting TBK1-dependent HPIP degradation

Shostak, K. and Patrascu, F. and Göktuna, S. I. and Close, P. and Borgs, L. and Nguyen, L. and Olivier, F. and Rammal, A. and Brinkhaus, H. and Bentires-Alj, M. and Marine, J.-C. and Chariot, A.. (2014) MDM2 restrains estrogen-mediated AKT activation by promoting TBK1-dependent HPIP degradation. Cell Death & Differentiation subscription, 21 (5). pp. 811-824.

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Official URL: https://edoc.unibas.ch/61379/

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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.
Faculties and Departments:03 Faculty of Medicine > Departement Biomedizin > Department of Biomedicine, University Hospital Basel > Tumor Heterogeneity Metastasis and Resistance (Bentires-Alj)
UniBasel Contributors:Bentires-Alj, Mohamed
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Nature Publishing Group
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:09 Dec 2020 16:59
Deposited On:09 Dec 2020 16:59

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