Hey1- and p53-dependent TrkC proapoptotic activity controls neuroblastoma growth

• DOI: 10.1371/journal.pbio.2002912
• Publication Date: 2018-05-11T17:27:42Z
• Authors: Marie Ménard; Clélia Costechareyre; Gabriel Ichim; Jonathan Blachier; David Neves; Loraine Jarrosson...; Reinhard Depping; Jan Koster; Pierre Saintigny; Patrick Mehlen; Servane Tauszig-D...
• Keywords: 0301 basic medicine; QH301-705.5; Apoptosis; Proto-Oncogene Proteins c-mdm2; [SDV.BC]Life Sciences [q-bio]/Cellular Biology; Chick Embryo; Karyopherins; HCT116 Cells; Chromatin; Repressor Proteins; Mice; Neuroblastoma; 03 medical and health sciences; HEK293 Cells; Gene Expression Regulation; Basic Helix-Loop-Helix Transcription Factors; Animals; Humans; Receptor, trkC; Biology (General); Tumor Suppressor Protein p53; Research Article

The neurotrophin-3 (NT-3) receptor tropomyosin kinase C (TrkC/NTRK3) has been described as a dependence and, such, triggers apoptosis in the absence of its ligand NT-3. This proapoptotic activity proposed to confer tumor suppressor this classic tyrosine (RTK). By investigating interacting partners that might facilitate TrkC-induced cell death, we have identified basic helix-loop-helix (bHLH) transcription factor Hey1 and importin-α3 (karyopherin alpha 4 [KPNA4]) direct interactors TrkC intracellular domain, show is required for apoptosis. We propose here cleaved portion domain (called killer-fragment [TrkC-KF]) translocated nucleus by importins interacts there with Hey1. also demonstrate TrkC-KF transcriptionally silence mouse double minute 2 homolog (MDM2), thus contributing p53 stabilization. regulates expression cytoplasmic mitochondrial cofactor breast cancer 1 (COBRA1) B lymphoma 2–associated X (BAX), which will subsequently trigger intrinsic pathway Of interest, was constrain progression neuroblastoma (NB), an avian model requires p53.