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Protein kinase D, ubiquitin and proteasome pathways are involved in adenosine receptor-stimulated NR4A expression in myeloid cells*

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dc.contributor.author Giffney, Hugh E.
dc.contributor.author Cummins, Eoin P.
dc.contributor.author Murphy, Evelyn P
dc.contributor.author Brayden, David J.
dc.contributor.author Crean, Daniel
dc.date.accessioned 2021-04-08T10:09:36Z
dc.date.available 2021-04-08T10:09:36Z
dc.date.issued 2021
dc.identifier.uri http://hdl.handle.net/10344/9973
dc.description peer-reviewed en_US
dc.description.abstract Adenosine is a purine nucleoside pivotal for homeostasis in cells and tissues. Stimulation of the adenosine receptors (AR) has been shown to regulate the nuclear orphan receptor 4A (NR4A1-3) family, resulting in attenuation of hyper-inflammatory responses in myeloid cells. The NR4A1-3 orphan receptors are early immediate response genes and transcriptional regulators of cell and tissue homeostasis. The signal transduction and transcriptional mechanism(s) of how AR-stimulation promotes NR4A expression in myeloid cells is unknown and is the focus of this study. We confirm that adenosine and the stable analogue, 50 -N-Ethylcarboxamidoadenosine (NECA), enhance NR4A1-3 expression in THP-1 cells. Pharmacological approaches identified that protein kinase D (PKD) mediates AR-stimulated NR4A expression in myeloid cells and reveals no involvement of PKA nor PKC. The role of NF-kB, a principal regulator of NR4A expression in myeloid cells, was examined as a possible transcriptional regulator downstream of PKD. Utilising BAY11-7082 and MG-132, inhibitors of the respective ubiquitin and pro teasome pathways essential for NF-kB activation, suggested a prospective role for NF-kB, or more specifically signalling via IKKa/b. However, biological interventional studies using overexpression of IkBa in myeloid cells and MEF cells lacking IKKa and IKKb (IKKa/b /-) revealed the NF-kB pathway is not utilised in mediating AR-stimulated NR4A expression. Thus, this study contributes mechanistic insight into how AR signalling modulates the expression of NR4A receptors, pivotal regulators of inflammatory responses in myeloid cells. en_US
dc.language.iso eng en_US
dc.publisher Elsevier en_US
dc.relation.ispartofseries Biochemical and Biophysical Research Communications;555, pp.19-25
dc.subject NR4A en_US
dc.subject Adenosine en_US
dc.title Protein kinase D, ubiquitin and proteasome pathways are involved in adenosine receptor-stimulated NR4A expression in myeloid cells* en_US
dc.type info:eu-repo/semantics/article en_US
dc.type.supercollection all_ul_research en_US
dc.type.supercollection ul_published_reviewed en_US
dc.identifier.doi 10.1016/j.bbrc.2021.03.082
dc.contributor.sponsor SFI en_US
dc.contributor.sponsor European Union (EU) en_US
dc.contributor.sponsor UCD en_US
dc.relation.projectid 13/RC/2073 en_US
dc.rights.accessrights info:eu-repo/semantics/openAccess en_US


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