TY - JOUR
T1 - The dependence receptor Ret induces apoptosis in somatotrophs through a Pit-1/p53 pathway, preventing tumor growth
AU - Cañibano, Carmen
AU - Rodriguez, Noela L.
AU - Saez, Carmen
AU - Tovar, Sulay
AU - Garcia-Lavandeira, Montse
AU - Borrello, Maria Grazia
AU - Vidal, Anxo
AU - Costantini, Frank
AU - Japon, Miguel
AU - Dieguez, Carlos
AU - Alvarez, Clara V.
PY - 2007/4/18
Y1 - 2007/4/18
N2 - 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.
AB - 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.
KW - c/EBPa
KW - Caspase-3
KW - GDNF
KW - Pituitary
KW - PKCd
UR - http://www.scopus.com/inward/record.url?scp=34247192417&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=34247192417&partnerID=8YFLogxK
U2 - 10.1038/sj.emboj.7601636
DO - 10.1038/sj.emboj.7601636
M3 - Article
C2 - 17380130
AN - SCOPUS:34247192417
VL - 26
SP - 2015
EP - 2028
JO - EMBO Journal
JF - EMBO Journal
SN - 0261-4189
IS - 8
ER -