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          Institute: MPI für medizinische Forschung     Collection: Abteilung Molekulare Neurobiologie     Display Documents

ID: 545946.0, MPI für medizinische Forschung / Abteilung Molekulare Neurobiologie
Involvement of Transducer of Regulated cAMP Response Element−Binding Protein Activity on Corticotropin Releasing Hormone Transcription
Translation of Title:Involvement of Transducer of Regulated cAMP Response Element−Binding Protein Activity on Corticotropin Releasing Hormone Transcription
Authors:Liu, Yuhong; Coello, Anna G.; Grinevich, Valery; Aguilera, Greti
Date of Publication (YYYY-MM-DD):2010-03-01
Title of Journal:Endocrinology
Journal Abbrev.:Endocrinology
Issue / Number:3
Start Page:1109
End Page:1118
Review Status:Peer-review
Audience:Experts Only
Intended Educational Use:No
Abstract / Description:We have recently shown that phospho−cAMP response element−binding protein (CREB) is essential
but not sufficient for activation of CRH transcription, suggesting the requirement of a coactivator.
Here, we test the hypothesis that the CREB coactivator, transducer of regulated CREB activity
(TORC), is required for activation of CRH transcription, using the cell line 4B and primary cultures
of hypothalamic neurons. Immunohistochemistry and Western blot experiments in 4B cells revealed
time−dependent nuclear translocation of TORC1,TORC 2, and TORC3 by forskolin [but not
by the phorbol ester, phorbol 12−myristate 13−acetate (PMA)] in a concentration−dependent manner.
In reporter gene assays, cotransfection of TORC1 or TORC2 potentiated the stimulatory effect
of forskolin on CRH promoter activity but had no effect in cells treated with PMA. Knockout of
endogenous TORC using silencing RNA markedly inhibited forskolin−activated CRH promoter activity
in 4B cells, as well as the induction of endogenous CRH primary transcript by forskolin in
primary neuronal cultures. Coimmunoprecipitation and chromatin immunoprecipitation experiments
in 4B cells revealed association of CREB and TORC in the nucleus, and recruitment of TORC2
by the CRH promoter, after 20−min incubation with forskolin. These studies demonstrate a correlation
between nuclear translocation of TORC with association to the CRH promoter and activation
of CRH transcription. The data suggest that TORC is required for transcriptional activation of the
CRH promoter by acting as a CREB coactivator. In addition, cytoplasmic retention of TORC during
PMAtreatment is likely to explain the failure of phorbolesters to activate CRH transcription in spite
of efficiently phosphorylating CREB.
Last Change of the Resource (YYYY-MM-DD):--
External Publication Status:published
Document Type:Article
Communicated by:Wulf Kaiser
Affiliations:MPI für medizinische Forschung/Abteilung Zellphysiologie
MPI für medizinische Forschung/Abteilung Molekulare Neurobiologie
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