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

被引：203

作者：

Bordeaux, MC

Forcet, C

Granger, L

Corset, V

Bidaud, C

Billaud, M

Bredesen, DE

Edery, P

Mehlen, P ^{[1
]}

机构：

[1] Univ Lyon 1, Lab Apoptose & Differenciat, F-69622 Villeurbanne, France

[2] Univ Lyon 1, Ctr Genet Mol & Cellulaire, CNRS, UMR 5534, F-69622 Villeurbanne, France

[3] CNRS, UMR 5641, Genet Lab, F-69373 Lyon, France

[4] Hop Hotel Dieu, Serv Genet Med, F-69288 Lyon 02, France

[5] Buck Ctr Res Aging, Program Aging, Novato, CA 94945 USA

[6] Burnham Inst, La Jolla, CA 92037 USA

[7] Univ Calif San Diego, Dept Neurosci, San Diego, CA 92093 USA

来源：

EMBO JOURNAL | 2000年 / 19卷 / 15期

关键词：

apoptosis; caspase; Hirschsprung; RET; tyrosine kinase receptor;

D O I：

10.1093/emboj/19.15.4056

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

The RET (rearranged during transfection) protooncogene 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.

引用

页码：4056 / 4063

页数：8