Glial cell line-derived neurotrophic factor induces proliferative inhibition of NT2/D1 cells through RET-mediated up-regulation of the cyclin-dependent kinase inhibitor p27kip1

Gustavo Baldassarre, Paola Bruni, Angelo Boccia, Giuliana Salvatore, Rosa Marina Melillo, Maria Letizia Motti, Maria Napolitano, Barbara Belletti, Alfredo Fusco, Massimo Santoro, Giuseppe Viglietto

Research output: Contribution to journalArticlepeer-review

Abstract

Growth factors of the glial cell line-derived neurotrophic factor (GDNF) family control the differentiation of neuronal cells of the central and peripheral nervous systems. Intracellular signalling of these growth factors is, at least in part, mediated by activation of the RET receptor tyrosine kinase. Here, we demonstrate that GDNF triggering inhibits the proliferation of the embryonal carcinoma cell line NT2/D1. This anti-proliferative effect is accompanied by down-regulation of the SSEA-3 antigen, a marker typical of undifferentiated NT2/D1 cells. We show that these effects are mediated by activation of RET signalling. The block of RET by a kinase-deficient dominant negative mutant impairs GDNF-dependent growth inhibition, whereas the adoptive expression of a constitutively active RET, the RET-MEN2A oncogene, promotes effects similar to those exerted by GDNF. We show that RET signalling increases the expression of the cyclin-dependent kinase inhibitor p27kip1 in NT2/D1 cells. Both DNA synthesis inhibition and SSEA-3 down-regulation are prevented if p27kip1 expression is blocked by an antisense construct, which demonstrates that RET-triggered effects are mediated by p27kip1.

Original languageEnglish
Pages (from-to)1739-1749
Number of pages11
JournalOncogene
Volume21
Issue number11
DOIs
Publication statusPublished - Mar 7 2002

Keywords

  • Embryonal carcinoma
  • GDNF
  • p27
  • RET

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

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