The dependence receptor Ret induces apoptosis in somatotrophs through a Pit-1/p53 pathway, preventing tumor growth

Carmen Cañibano, Noela L. Rodriguez, Carmen Saez, Sulay Tovar, Montse Garcia-Lavandeira, Maria Grazia Borrello, Anxo Vidal, Frank Costantini, Miguel Japon, Carlos Dieguez, Clara V. Alvarez

Research output: Contribution to journalArticlepeer-review

Abstract

Somatotrophs are the only pituitary cells that express Ret, GFRα1 and GDNF. This study investigated the effects of Ret in a somatotroph cell line, in primary pituitary cultures and in Ret KO mice. Ret regulates somatotroph numbers by inducing Pit-1 overexpression, leading to increased p53 expression and apoptosis, both of which can be prevented with Ret or Pit-1 siRNA. The Pit-1 overexpression is mediated by sustained activation of PKCδ, JNK, c/EBPα and CREB induced by a complex of Ret, caspase 3 and PKCδ. In the presence of GDNF, Akt is activated, and the Pit-1 overexpression and resulting apoptosis are blocked. The adenopituitary of Ret KO mice is larger than normal, showing Pit-1 and somatotroph hyperplasia. In normal animals, activation of the Ret/Pit-1/p53 pathway by retroviral introduction of Ret blocked tumor growth in vivo. Thus, somatotrophs have an intrinsic mechanism for controlling Pit-1/GH production through an apoptotic/survival pathway. Ret might be of value for treatment of pituitary adenomas.

Original languageEnglish
Pages (from-to)2015-2028
Number of pages14
JournalEMBO Journal
Volume26
Issue number8
DOIs
Publication statusPublished - Apr 18 2007

Keywords

  • c/EBPa
  • Caspase-3
  • GDNF
  • Pituitary
  • PKCd

ASJC Scopus subject areas

  • Genetics
  • Cell Biology

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