Premium
The dependence receptor Ret induces apoptosis in somatotrophs through a Pit‐1/p53 pathway, preventing tumor growth
Author(s) -
Cañibano Carmen,
Rodriguez Noela L,
Saez Carmen,
Tovar Sulay,
GarciaLavandeira Montse,
Borrello Maria Grazia,
Vidal Anxo,
Costantini Frank,
Japon Miguel,
Dieguez Carlos,
Alvarez Clara V
Publication year - 2007
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/sj.emboj.7601636
Subject(s) - biology , apoptosis , cancer research , receptor , microbiology and biotechnology , signal transduction , medicine , genetics
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.