Nerve growth factor receptor negates the tumor suppressor p53 as a feedback regulator.
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.
Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, New Orleans, United States.|Tulane Cancer Center, Tulane University School of Medicine, New Orleans, United States.
Xiang
X
Zhou
Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, New Orleans, United States.|Tulane Cancer Center, Tulane University School of Medicine, New Orleans, United States.
Qian
Q
Hao
Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, New Orleans, United States.|Tulane Cancer Center, Tulane University School of Medicine, New Orleans, United States.
Peng
P
Liao
Center for Experimental Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, China.
Shiwen
S
Luo
Center for Experimental Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, China.
Minhong
M
Zhang
Center for Experimental Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, China.
Guohui
G
Hu
Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, New Orleans, United States.|Tulane Cancer Center, Tulane University School of Medicine, New Orleans, United States.
Hongbing
H
Liu
Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, New Orleans, United States.|Tulane Cancer Center, Tulane University School of Medicine, New Orleans, United States.
Yiwei
Y
Zhang
Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, New Orleans, United States.|Tulane Cancer Center, Tulane University School of Medicine, New Orleans, United States.
Bo
B
Cao
Tulane Cancer Center, Tulane University School of Medicine, New Orleans, United States.
Melody
M
Baddoo
Tulane Cancer Center, Tulane University School of Medicine, New Orleans, United States.
Erik K
EK
Flemington
Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, New Orleans, United States.|Tulane Cancer Center, Tulane University School of Medicine, New Orleans, United States.
Shelya X
SX
Zeng
Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, New Orleans, United States.|Tulane Cancer Center, Tulane University School of Medicine, New Orleans, United States.
Hua
0000-0002-9285-7209
H
Lu
D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D002470:Cell Survival; D004195:Disease Models, Animal; D025461:Feedback, Physiological; D005786:Gene Expression Regulation; D005909:Glioblastoma / Q000503:physiopathology; D064593:Heterografts; D006801:Humans; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D017475:Receptors, Nerve Growth Factor / Q000378:metabolism*; D014410:Tumor Stem Cell Assay; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
C484065:NGFR protein, human; D009419:Nerve Tissue Proteins; D017475:Receptors, Nerve Growth Factor; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2
MDM2; NGFR; cancer biology; cell biology; cell viability; human; p53; protein stability; transcriptional regulation