Nerve growth factor receptor negates the tumor suppressor p53 as a feedback regulator
- Fudan University, China
- Tulane University School of Medicine, United States
- The First Affiliated Hospital of Nanchang University, China
Abstract
Cancer develops and progresses often by inactivating p53. Here, we unveil nerve growth factor receptor (NGFR, CD271 or p75NTR) as a novel p53 inactivator. p53 activates NGFR transcription, whereas NGFR inactivates p53 by promoting its MDM2-mediated ubiquitin-dependent proteolysis and by directly binding to its central DNA binding domain and preventing its DNA-binding activity. Inversely, NGFR ablation activates p53, consequently inducing apoptosis, attenuating survival, and reducing clonogenic capability of cancer cells, as well as sensitizing human cancer cells to chemotherapeutic agents that induce p53 and suppressing mouse xenograft tumor growth. NGFR is highly expressed in human glioblastomas, and its gene is often amplified in breast cancers with wild type p53. Altogether, our results demonstrate that cancers hijack NGFR as an oncogenic inhibitor of p53.
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Ethics
Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (#4257R) of Tulane University School of Medicine.
Copyright
© 2016, Zhou et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Nerve growth factor receptor negates the tumor suppressor p53 as a feedback regulator
eLife 5:e15099.
https://doi.org/10.7554/eLife.15099
