Regulation of cAMP Responsive Element Binding Protein 3-Like 1 (Creb3l1) Expression by Orphan Nuclear Receptor Nr4a1
Cyclic AMP (cAMP) inducible transcription factor cAMP responsive element binding protein 3 like 1 (Creb3l1) is strongly activated in the hypothalamus in response to hyperosmotic cues such as dehydration (DH). We have recently shown that Creb3l1 expression is upregulated by cAMP pathways in vitro, ho...
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doaj-0782b9d5f599449da71098912a1529ca2020-11-24T20:40:14ZengFrontiers Media S.A.Frontiers in Molecular Neuroscience1662-50992017-12-011010.3389/fnmol.2017.00413298271Regulation of cAMP Responsive Element Binding Protein 3-Like 1 (Creb3l1) Expression by Orphan Nuclear Receptor Nr4a1Michael P. Greenwood0Mingkwan Greenwood1Benjamin T. Gillard2R. Chitra Devi3David Murphy4David Murphy5School of Clinical Sciences, University of Bristol, Bristol, United KingdomSchool of Clinical Sciences, University of Bristol, Bristol, United KingdomSchool of Clinical Sciences, University of Bristol, Bristol, United KingdomDepartment of Physiology, Faculty of Medicine, University of Malaya, Kuala Lumpur, MalaysiaSchool of Clinical Sciences, University of Bristol, Bristol, United KingdomDepartment of Physiology, Faculty of Medicine, University of Malaya, Kuala Lumpur, MalaysiaCyclic AMP (cAMP) inducible transcription factor cAMP responsive element binding protein 3 like 1 (Creb3l1) is strongly activated in the hypothalamus in response to hyperosmotic cues such as dehydration (DH). We have recently shown that Creb3l1 expression is upregulated by cAMP pathways in vitro, however the exact mechanisms are not known. Here we show that increasing Creb3l1 transcription by raising cAMP levels in mouse pituitary AtT20 cells automatically initiates cleavage of Creb3l1, leading to a greater abundance of the transcriptionally active N-terminal portion. Inhibiting protein synthesis indicated that de novo protein synthesis of an intermediary transcription factor was required for Creb3l1 induction. Strategic mining of our microarray data from dehydrated rodent hypothalamus revealed four candidates, reduced to two by analysis of acute hyperosmotic-induced transcriptional activation profiles in the hypothalamus, and one, orphan nuclear receptor Nr4a1, by direct shRNA mediated silencing in AtT20 cells. We show that activation of Creb3l1 transcription by Nr4a1 involves interaction with a single NBRE site in the promoter region. The ability to activate Creb3l1 transcription by this pathway in vitro is dictated by the level of methylation of a CpG island within the proximal promoter/5′UTR of this gene. We thus identify a novel cAMP-Nr4a1-Creb3l1 transcriptional pathway in AtT20 cells and also, our evidence would suggest, in the hypothalamus.http://journal.frontiersin.org/article/10.3389/fnmol.2017.00413/fullvasopressincAMPtranscription factorstranscriptional activationhypothalamusmethylation |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Michael P. Greenwood Mingkwan Greenwood Benjamin T. Gillard R. Chitra Devi David Murphy David Murphy |
spellingShingle |
Michael P. Greenwood Mingkwan Greenwood Benjamin T. Gillard R. Chitra Devi David Murphy David Murphy Regulation of cAMP Responsive Element Binding Protein 3-Like 1 (Creb3l1) Expression by Orphan Nuclear Receptor Nr4a1 Frontiers in Molecular Neuroscience vasopressin cAMP transcription factors transcriptional activation hypothalamus methylation |
author_facet |
Michael P. Greenwood Mingkwan Greenwood Benjamin T. Gillard R. Chitra Devi David Murphy David Murphy |
author_sort |
Michael P. Greenwood |
title |
Regulation of cAMP Responsive Element Binding Protein 3-Like 1 (Creb3l1) Expression by Orphan Nuclear Receptor Nr4a1 |
title_short |
Regulation of cAMP Responsive Element Binding Protein 3-Like 1 (Creb3l1) Expression by Orphan Nuclear Receptor Nr4a1 |
title_full |
Regulation of cAMP Responsive Element Binding Protein 3-Like 1 (Creb3l1) Expression by Orphan Nuclear Receptor Nr4a1 |
title_fullStr |
Regulation of cAMP Responsive Element Binding Protein 3-Like 1 (Creb3l1) Expression by Orphan Nuclear Receptor Nr4a1 |
title_full_unstemmed |
Regulation of cAMP Responsive Element Binding Protein 3-Like 1 (Creb3l1) Expression by Orphan Nuclear Receptor Nr4a1 |
title_sort |
regulation of camp responsive element binding protein 3-like 1 (creb3l1) expression by orphan nuclear receptor nr4a1 |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Molecular Neuroscience |
issn |
1662-5099 |
publishDate |
2017-12-01 |
description |
Cyclic AMP (cAMP) inducible transcription factor cAMP responsive element binding protein 3 like 1 (Creb3l1) is strongly activated in the hypothalamus in response to hyperosmotic cues such as dehydration (DH). We have recently shown that Creb3l1 expression is upregulated by cAMP pathways in vitro, however the exact mechanisms are not known. Here we show that increasing Creb3l1 transcription by raising cAMP levels in mouse pituitary AtT20 cells automatically initiates cleavage of Creb3l1, leading to a greater abundance of the transcriptionally active N-terminal portion. Inhibiting protein synthesis indicated that de novo protein synthesis of an intermediary transcription factor was required for Creb3l1 induction. Strategic mining of our microarray data from dehydrated rodent hypothalamus revealed four candidates, reduced to two by analysis of acute hyperosmotic-induced transcriptional activation profiles in the hypothalamus, and one, orphan nuclear receptor Nr4a1, by direct shRNA mediated silencing in AtT20 cells. We show that activation of Creb3l1 transcription by Nr4a1 involves interaction with a single NBRE site in the promoter region. The ability to activate Creb3l1 transcription by this pathway in vitro is dictated by the level of methylation of a CpG island within the proximal promoter/5′UTR of this gene. We thus identify a novel cAMP-Nr4a1-Creb3l1 transcriptional pathway in AtT20 cells and also, our evidence would suggest, in the hypothalamus. |
topic |
vasopressin cAMP transcription factors transcriptional activation hypothalamus methylation |
url |
http://journal.frontiersin.org/article/10.3389/fnmol.2017.00413/full |
work_keys_str_mv |
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