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

PLoS Biology
Marie MénardServane Tauszig-Delamasure

Abstract

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

References

Apr 1, 1992·Nature Genetics·W S el-DeiryB Vogelstein
Jan 1, 1997·Journal of Neuro-oncology·G M BrodeurA E Evans
Jun 8, 2000·BioEssays : News and Reviews in Molecular, Cellular and Developmental Biology·D A JansM H Lam
Dec 26, 2001·Current Opinion in Structural Biology·Y M Chook, G Blobel
Apr 5, 2002·Nature·Ina RheeBert Vogelstein
Jul 4, 2003·The Journal of Biological Chemistry·Yoshihito TaniguchiSangram S Sisodia
Sep 16, 2003·Journal of Cell Science·Susan HauptYgal Haupt
Mar 3, 2004·Proceedings of the National Academy of Sciences of the United States of America·Qihong HuangPeter G Schultz
Apr 27, 2004·Genes & Development·Andreas FischerManfred Gessler
Aug 18, 2004·Proceedings of the National Academy of Sciences of the United States of America·Loen M HansfordGlenn M Marshall
Oct 8, 2004·Critical Care : the Official Journal of the Critical Care Forum·Viv BewickJonathan Ball
Feb 3, 2005·Molecular and Cellular Biology·Borja BelandiaMalcolm G Parker
Jan 7, 2006·Nature·Dwayne G StupackDavid A Cheresh
Aug 31, 2006·Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences·Louis F Reichardt
Oct 5, 2006·Cancer Research·Tom Van MaerkenJo Vandesompele
Jan 24, 2007·Nature Reviews. Neuroscience·Frédéric Marmigère, Patrik Ernfors
Jun 26, 2007·Lancet·John M MarisSusan L Cohn
Aug 10, 2007·Proceedings of the National Academy of Sciences of the United States of America·Servane Tauszig-DelamasurePatrick Mehlen
Apr 9, 2008·Molecular and Cellular Biology·David GoldschneiderPatrick Mehlen
Oct 17, 2008·Nature·Isabelle Janoueix-LeroseyOlivier Delattre
Jul 18, 2009·The American Journal of Pathology·Goleeta AlamHan-Fei Ding
Jul 28, 2009·Developmental Biology·Abhishek MukhopadhyayJohn A Kessler
Feb 11, 2010·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Jane Carr-WilkinsonDeborah A Tweddle
Feb 18, 2010·The Journal of Clinical Investigation·Jimena Bouzas-RodriguezPatrick Mehlen
Mar 20, 2010·Cold Spring Harbor Perspectives in Biology·Marie P Khoury, Jean-Christophe Bourdon
Sep 3, 2010·Nature·Vassiliki NikoletopoulouYves-Alain Barde
Apr 9, 2011·Expert Opinion on Therapeutic Targets·Servane Tauszig-Delamasure, Jimena Bouzas-Rodriguez
Dec 1, 2011·Cell Cycle·Krassimira BotchevaCarl W Anderson
Jan 24, 2013·Proceedings of the National Academy of Sciences of the United States of America·Anne-Laure GenevoisPatrick Mehlen
Feb 12, 2013·Proceedings of the National Academy of Sciences of the United States of America·William M Grady
Apr 6, 2013·Science·Martijn P J Dekkers, Yves-Alain Barde
Aug 29, 2014·Gut·Patrick Mehlen, Servane Tauszig-Delamasure
Sep 25, 2014·Current Topics in Developmental Biology·David WeberManfred Gessler
Dec 3, 2014·Journal of Molecular and Cellular Cardiology·David WeberManfred Gessler
Dec 21, 2014·Cancer Discovery·Aria VaishnaviRobert C Doebele

❮ Previous
Next ❯

Citations

Aug 23, 2018·Oncotarget·Natalia Kalinina
Oct 24, 2019·Cell Communication and Signaling : CCS·Filip VujovicRamin M Farahani
Sep 25, 2020·Modern Pathology : an Official Journal of the United States and Canadian Academy of Pathology, Inc·Arnaud de la FouchardièreIwei Yeh
Nov 26, 2020·American Journal of Physiology. Gastrointestinal and Liver Physiology·Lei ZhengLiming Gao
Sep 3, 2021·Proceedings of the National Academy of Sciences of the United States of America·Yan SunAndrea Paradisi

❮ Previous
Next ❯

Methods Mentioned

BETA
2-hybrid
nuclear translocation
proximity ligation assay
proximity ligation
transfection
confocal microscopy
Immunoprecipitation
PCR
proximity
ChIP

Software Mentioned

GraphPad
BiostaTGV
ImageJ64
Prism
R2 Genomics Analysis and Visualization Platform

Related Concepts

Related Feeds

Apoptosis

Apoptosis is a specific process that leads to programmed cell death through the activation of an evolutionary conserved intracellular pathway leading to pathognomic cellular changes distinct from cellular necrosis

Apoptosis in Cancer

Apoptosis is an important mechanism in cancer. By evading apoptosis, tumors can continue to grow without regulation and metastasize systemically. Many therapies are evaluating the use of pro-apoptotic activation to eliminate cancer growth. Here is the latest research on apoptosis in cancer.

CRISPR (general)

Clustered regularly interspaced short palindromic repeats (CRISPR) are DNA sequences in the genome that are recognized and cleaved by CRISPR-associated proteins (Cas). CRISPR-Cas system enables the editing of genes to create or correct mutations. Discover the latest research on CRISPR here.

Anthelmintics (ASM)

Anthelmintics or antihelminthics are a group of antiparasitic drugs that expel parasitic worms (helminths) and other internal parasites from the body by either stunning or killing them and without causing significant damage to the host. Discover the latest research on anthelmintics here.

CREs: Gene & Cell Therapy

Gene and cell therapy advances have shown promising outcomes for several diseases. The role of cis-regulatory elements (CREs) is crucial in the design of gene therapy vectors. Here is the latest research on CREs in gene and cell therapy.

Cell Signaling by Tyrosine Kinases

Receptor tyrosine kinases (RTKs) are the high-affinity cell surface receptors for many polypeptide growth factors, cytokines, and hormones. RTKs have been shown not only to be key regulators of normal cellular processes but also to have a critical role in the development and progression of many types of cancer. Discover the latest research on cell signaling and RTK here.

B-Cell Lymphoma

B-cell lymphomas include lymphomas that affect B cells. This subtype of cancer accounts for over 80% of non-Hodgkin lymphomas in the US. Here is the latest research.

Breast Tumorigenesis

Breast tumorigenesis involves the production or formation of tumor(s) in breast tissue. Discover the latest research on breast tumorigenesis here.

CRISPR Ribonucleases Deactivation

CRISPR-Cas system enables the editing of genes to create or correct mutations. This feed focuses on mechanisms that underlie deactivation of CRISPR ribonucleases. Here is the latest research.

Apoptotic Caspases

Apoptotic caspases belong to the protease enzyme family and are known to play an essential role in inflammation and programmed cell death. Here is the latest research.

CRISPR Genome Editing & Therapy

CRISPR-Cas system enables the editing of genes to create or correct mutations. This feed focuses on the application of this system for gene editing and therapy in human diseases.

CRISPR in Cancer

CRISPR-Cas system enables the editing of genes to create or correct mutations. Given that genome instability and mutation is one of the hallmarks of cancer, the CRISPR-Cas system is being explored to genetically alter and eliminate cancer cells. Here is the latest research.

Anthelmintics

Anthelmintics or antihelminthics are a group of antiparasitic drugs that expel parasitic worms (helminths) and other internal parasites from the body by either stunning or killing them and without causing significant damage to the host. Discover the latest research on anthelmintics here.