Abstract
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.
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Abbreviations
- CAS:
-
Cellular apoptosis susceptibility
- EGF:
-
Epithelial growth factor
- ERα:
-
Estrogen receptor alpha
- GREB1:
-
Growth regulation by estrogen in breast cancer 1
- FOXO3a:
-
Forkhead box O3
- HPIP:
-
Microtubule-binding protein hematopoietic PBX-interaction protein
- HUWE1:
-
HECT, UBA and WWE domain-containing protein 1
- IKK:
-
I kappaB alpha kinase
- MDM2:
-
Mouse double minute 2
- MEC:
-
Mammary epithelial cell
- NAP1:
-
NAK (NF-kappaB-activating kinase)-associated protein 1
- NEMO:
-
NF-kappa B essential modulator
- PBX1:
-
Pre-B-cell leukemia homeobox protein 1
- PCR:
-
Polymerase chain reaction
- PI3K:
-
Phosphatidylinositide 3-kinase
- TANK:
-
TRAF family member associated NF-kappaB activator
- TBK1:
-
TANK-binding kinase 1
- TNFα:
-
Tumor necrosis factor alpha
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Acknowledgements
We are grateful to E Dejardin for helpful discussions and to the GIGA Imaging and Flow Cytometry Platform for performing the FACS and IF analyses. This work was supported by grants from the FNRS, TELEVIE, the Belgian Federation against cancer, the King Baudouin Fundation, the University of Liege (Concerted Research Action Program (BIO-ACET) and ‘Fonds Spéciaux’, the Inter-University Attraction Pole 6/12 (Federal Ministery of Science), the ‘Plan Cancer (Action 29)’, the ‘Centre Anti-Cancéreux’ and the ‘Leon Fredericq’ Fundation (ULg) as well as by the Walloon Excellence in Life Sciences and Biotechnology (WELBIO). PC, LN and AC are Research Associates and Senior Research Associate at the Belgian National Funds for Scientific Research (FNRS), respectively.
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Shostak, K., Patrascu, F., Göktuna, S. et al. MDM2 restrains estrogen-mediated AKT activation by promoting TBK1-dependent HPIP degradation. Cell Death Differ 21, 811–824 (2014). https://doi.org/10.1038/cdd.2014.2
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DOI: https://doi.org/10.1038/cdd.2014.2
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