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Elife. 2016 Jun 10;5. pii: e15099. doi: 10.7554/eLife.15099.

Nerve growth factor receptor negates the tumor suppressor p53 as a feedback regulator.

Author information

1
Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, New Orleans, United States.
2
Tulane Cancer Center, Tulane University School of Medicine, New Orleans, United States.
3
Center for Experimental Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, China.

Abstract

Cancer develops and progresses often by inactivating p53. Here, we unveil nerve growth factor receptor (NGFR, p75NTR or CD271) 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.

KEYWORDS:

MDM2; NGFR; cancer biology; cell biology; cell viability; human; p53; protein stability; transcriptional regulation

PMID:
27282385
PMCID:
PMC4943851
DOI:
10.7554/eLife.15099
[Indexed for MEDLINE]
Free PMC Article

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