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The RET proto-oncogene induces apoptosis: a novel mechanism for Hirschsprung disease

M C Bordeaux1, C Forcet, L Granger

  • 1Laboratoire Apoptose et Différenciation, label La Ligue contre le Cancer et Laboratoire de Génétique Humaine - Centre de Génétique Moléculaire et Cellulaire, CNRS UMR 5534, Université Lyon 1, 69622 Villeurbanne, France.

The EMBO Journal
|August 2, 2000
PubMed

Insights

The rearranged during transfection (RET) receptor normally induces cell death (apoptosis), but its ligand, glial cell line-derived neurotrophic factor (GDNF), inhibits this. Hirschsprung-associated RET mutations disrupt this control, potentially causing enteric neuroblast apoptosis.

Area of Science:

  • Molecular Biology
  • Developmental Biology
  • Oncology

Background:

  • The RET proto-oncogene encodes a tyrosine kinase receptor crucial for development and implicated in cancer.
  • RET is associated with inherited cancer syndromes like multiple endocrine neoplasia type 2 (MEN 2) and developmental defects such as Hirschsprung disease (HSCR).

Purpose of the Study:

  • To investigate the role of RET receptor expression in apoptosis.
  • To determine the effect of glial cell line-derived neurotrophic factor (GDNF) on RET-induced apoptosis.
  • To examine the impact of Hirschsprung-associated RET mutations on GDNF's modulation of RET's pro-apoptotic activity.

Main Methods:

  • Investigating RET receptor expression and its effect on apoptosis.
  • Analyzing the interaction between RET, its ligand GDNF, and caspase activity.
  • Studying the functional consequences of specific RET mutations found in Hirschsprung disease.

Main Results:

  • RET receptor expression was found to induce apoptosis.
  • The pro-apoptotic effect of RET is inhibited by its ligand, GDNF.
  • RET undergoes caspase-mediated cleavage, releasing a pro-apoptotic domain.
  • Hirschsprung-associated RET mutations impair GDNF's ability to inhibit RET-induced apoptosis.

Conclusions:

  • RET-induced apoptosis is a regulated process modulated by GDNF.
  • Caspase-mediated cleavage of RET is a key mechanism in its pro-apoptotic function.
  • Dysregulation of RET-induced apoptosis due to specific mutations may underlie the pathogenesis of Hirschsprung disease.

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