Inhibition of tumor suppressor p73 by nerve growth factor receptor via chaperone-mediated autophagy

J Mol Cell Biol. 2020 Sep 1;12(9):700-712. doi: 10.1093/jmcb/mjaa017.

Abstract

The tumor suppressr p73 is a homolog of p53 and is capable of inducing cell cycle arrest and apoptosis. Here, we identify nerve growth factor receptor (NGFR, p75NTR, or CD271) as a novel negative p73 regulator. p73 activates NGFR transcription, which, in turn, promotes p73 degradation in a negative feedback loop. NGFR directly binds to p73 central DNA-binding domain and suppresses p73 transcriptional activity as well as p73-mediated apoptosis in cancer cells. Surprisingly, we uncover a previously unknown mechanism of NGFR-facilitated p73 degradation through the chaperone-mediated autophagy (CMA) pathway. Collectively, our studies demonstrate a new oncogenic function for NGFR in inactivating p73 activity by promoting its degradation through the CMA.

Keywords: HSPA8; Lamp2a; NGFR; chaperone-mediated autophagy; p73.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Cell Line, Tumor
  • Cell Proliferation
  • Chaperone-Mediated Autophagy*
  • Down-Regulation
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Protein Binding
  • Proteolysis
  • Proto-Oncogene Proteins c-mdm2 / metabolism
  • Receptor, Nerve Growth Factor / genetics
  • Receptor, Nerve Growth Factor / metabolism*
  • Transcription Factors
  • Transcriptional Activation / genetics
  • Tumor Protein p73 / antagonists & inhibitors*
  • Tumor Protein p73 / metabolism
  • Tumor Suppressor Proteins

Substances

  • Receptor, Nerve Growth Factor
  • TP63 protein, human
  • Transcription Factors
  • Tumor Protein p73
  • Tumor Suppressor Proteins
  • Proto-Oncogene Proteins c-mdm2