The RET proto-oncogene induces apoptosis: a novel mechanism for Hirschsprung disease.
The RET (rearranged during transfection) proto-oncogene encodes a tyrosine kinase receptor involved in both multiple endocrine neoplasia type 2 (MEN 2), an inherited cancer syndrome, and Hirschsprung disease (HSCR), a developmental defect of enteric neurons. We report here that the expression of RET receptor induces apoptosis. This pro-apoptotic effect of RET is inhibited in the presence of its ligand glial cell line-derived neurotrophic factor (GDNF). Furthermore, we present evidence that RET induces apoptosis via its own cleavage by caspases, a phenomenon allowing the liberation/exposure of a pro-apoptotic domain of RET. In addition, we report that Hirschsprung-associated RET mutations impair GDNF control of RET pro-apoptotic activity. These results indicate that HSCR may result from apoptosis of RET-expressing enteric neuroblasts.
Bordeaux
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MC
Laboratoire 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.
Forcet
C
C
Granger
L
L
Corset
V
V
Bidaud
C
C
Billaud
M
M
Bredesen
D E
DE
Edery
P
P
Mehlen
P
P
D017209:Apoptosis; D001342:Autonomic Nervous System Diseases / Q000209:etiology; D020169:Caspases / Q000378:metabolism; D029721:Drosophila Proteins; D017615:Enteric Nervous System / Q000473:pathology; D004789:Enzyme Activation; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D006627:Hirschsprung Disease / Q000209:etiology* / Q000235:genetics; D008024:Ligands; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D013379:Substrate Specificity
D029721:Drosophila Proteins; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D008024:Ligands; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D011518:Proto-Oncogene Proteins; D011994:Recombinant Proteins; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; C416649:Ret protein, Drosophila; D020169:Caspases