The dependence receptor Ret induces apoptosis in somatotrophs through a Pit-1/p53 pathway, preventing tumor growth.
Somatotrophs are the only pituitary cells that express Ret, GFRalpha1 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 PKCdelta, JNK, c/EBPalpha and CREB induced by a complex of Ret, caspase 3 and PKCdelta. 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.
Cañibano
Carmen
C
Department of Physiology, School of Medicine, University of Santiago de Compostela, Santiago de Compostela, Spain.
Rodriguez
Noela L
NL
Saez
Carmen
C
Tovar
Sulay
S
Garcia-Lavandeira
Montse
M
Borrello
Maria Grazia
MG
Vidal
Anxo
A
Costantini
Frank
F
Japon
Miguel
M
Dieguez
Carlos
C
Alvarez
Clara V
CV
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D015152:Blotting, Northern; D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D017931:DNA Primers; D005786:Gene Expression Regulation / Q000502:physiology*; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009369:Neoplasms / Q000378:metabolism* / Q000517:prevention & control; D051745:Protein Kinase C-delta / Q000378:metabolism; D051096:Proto-Oncogene Proteins c-ret / Q000378:metabolism*; D034622:RNA Interference; D051381:Rats; D015398:Signal Transduction / Q000502:physiology*; D052683:Somatotrophs / Q000378:metabolism*; D050817:Transcription Factor Pit-1 / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D017362:Cyclic AMP Response Element-Binding Protein; D017931:DNA Primers; D051100:Glial Cell Line-Derived Neurotrophic Factor; D050817:Transcription Factor Pit-1; D016159:Tumor Suppressor Protein p53; D051096:Proto-Oncogene Proteins c-ret; C495001:Ret protein, rat; D051745:Protein Kinase C-delta; D048670:MAP Kinase Kinase 4