MDM2 restrains estrogen-mediated AKT activation by promoting TBK1-dependent HPIP degradation.
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.
1] Interdisciplinary Cluster for Applied Genoproteomics, GIGA-Research, University of Liège, Liège, Belgium [2] Unit of Medical Chemistry, GIGA-Signal Transduction, GIGA-R, University of Liège, Liège, Belgium.
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Shostak
1] Interdisciplinary Cluster for Applied Genoproteomics, GIGA-Research, University of Liège, Liège, Belgium [2] Unit of Medical Chemistry, GIGA-Signal Transduction, GIGA-R, University of Liège, Liège, Belgium.
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Patrascu
1] Interdisciplinary Cluster for Applied Genoproteomics, GIGA-Research, University of Liège, Liège, Belgium [2] Unit of Medical Chemistry, GIGA-Signal Transduction, GIGA-R, University of Liège, Liège, Belgium.
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Göktuna
1] Interdisciplinary Cluster for Applied Genoproteomics, GIGA-Research, University of Liège, Liège, Belgium [2] Unit of Medical Chemistry, GIGA-Signal Transduction, GIGA-R, University of Liège, Liège, Belgium.
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Close
1] Interdisciplinary Cluster for Applied Genoproteomics, GIGA-Research, University of Liège, Liège, Belgium [2] Developmental Neurobiology Unit, GIGA-Neurosciences, GIGA-R, University of Liège, Liège, Belgium.
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Borgs
1] Interdisciplinary Cluster for Applied Genoproteomics, GIGA-Research, University of Liège, Liège, Belgium [2] Developmental Neurobiology Unit, GIGA-Neurosciences, GIGA-R, University of Liège, Liège, Belgium [3] Walloon Excellence in Life Sciences and Biotechnology (WELBIO), Wallonia, Belgium.
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Nguyen
1] Interdisciplinary Cluster for Applied Genoproteomics, GIGA-Research, University of Liège, Liège, Belgium [2] Animal Facility, University of Liege, CHU, Sart-Tilman, Liège 4000, Belgium.
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Olivier
1] Interdisciplinary Cluster for Applied Genoproteomics, GIGA-Research, University of Liège, Liège, Belgium [2] Unit of Medical Chemistry, GIGA-Signal Transduction, GIGA-R, University of Liège, Liège, Belgium.
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Rammal
Mechanisms of Cancer, Friedrich Miescher Institute for Biomedical Research (FMI), Basel, Switzerland.
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Brinkhaus
Mechanisms of Cancer, Friedrich Miescher Institute for Biomedical Research (FMI), Basel, Switzerland.
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Bentires-Alj
1] Center for Human Genetics, KU Leuven, Leuven, Belgium [2] Center for the biology of disease, VIB, KU Leuven, Leuven, Belgium.
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Marine
1] Interdisciplinary Cluster for Applied Genoproteomics, GIGA-Research, University of Liège, Liège, Belgium [2] Unit of Medical Chemistry, GIGA-Signal Transduction, GIGA-R, University of Liège, Liège, Belgium [3] Walloon Excellence in Life Sciences and Biotechnology (WELBIO), Wallonia, Belgium.
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Chariot
D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D047628:Estrogen Receptor alpha / Q000378:metabolism; D004967:Estrogens; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D061986:MCF-7 Cells; D051379:Mice; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D015398:Signal Transduction; D013629:Tamoxifen / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000378:metabolism
D047628:Estrogen Receptor alpha; D004967:Estrogens; D047908:Intracellular Signaling Peptides and Proteins; D016159:Tumor Suppressor Protein p53; D013629:Tamoxifen; C497206:MDM2 protein, human; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2; C498588:Tbk1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; C403191:TBK1 protein, human