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The '''G-CSF factor stem-loop destabilising element (SLDE)''' is an [[cis-regulatory element|RNA element]] secreted by [[fibroblast]]s and [[endothelial cells]] in response to the inflammatory mediators [[interleukin-1]] (IL-1) and [[tumour necrosis factor-alpha]] and by activated [[macrophage]]s. The synthesis of G-CSF is regulated both [[transcription (genetics)|transcriptionally]] and through control of [[mRNA]] stability. In unstimulated cells G-CSF mRNA is unstable but becomes stabilised in response to IL-1 or tumour necrosis factor alpha, and also in the case of [[monocyte]]s and macrophages, in response to [[lipopolysaccharide]]. It is likely that the presence of the SLDE in the G-CSF mRNA contributes to the specificity of regulation of G-CSF mRNA and enhances the rate of shortening of the [[polyadenylation|poly(A) tail]].<ref>{{cite journal | vauthors = Putland RA, Sassinis TA, Harvey JS, Diamond P, Coles LS, Brown CY, Goodall GJ | title = RNA destabilization by the granulocyte colony-stimulating factor stem-loop destabilizing element involves a single stem-loop that promotes deadenylation | journal = Molecular and Cellular Biology | volume = 22 | issue = 6 | pages = 1664–1673 | date = March 2002 | pmid = 11865046 | pmc = 135610 | doi = 10.1128/MCB.22.6.1664-1673.2002 }}</ref>
In[[AU-rich anotherelement|Adenylate studyuridylate-rich byelements]] Cheryl(AUREs) Yare Brownpresent etin other cytokine mRNAs, but the SLDE is the most important element that stabilizes G-CSF mRNA in response to IL-1 or tumor necrosis factor- alpha.al<ref>{{Citecite journal |last vauthors = Brown|first=C. Y.|last2=CY, Lagnado|first2=C. A.|last3=CA, Goodall|first3=G. J.|date=1996-11-26GJ | title = A cytokine mRNA-destabilizing element that is structurally and functionally distinct from A+U-rich elements |url=http://www.pnas.org/cgi/doi/10.1073/pnas.93.24.13721| journal = Proceedings of the National Academy of Sciences|language=en|volume=93|issue=24|pages=13721–13725|doi=10.1073/pnas.93.24.13721|issn=0027-8424|pmc=PMC19403|pmid=8943001}}</ref> showingof the importanceUnited States of theAmerica 3'UTR| elementvolume SLDE= of93 G-CSF| mRNAissue is= shown.24 AUREs| arepages shown= to13721–13725 be| presentdate in= otherNovember cytokine1996 mRNAs,| butpmid the= SLDE8943001 is| thepmc most= important19403 element| thatdoi stablizes= G-CSF10.1073/pnas.93.24.13721 mRNA| inbibcode response= to1996PNAS...9313721B IL| doi-1access or= tumor necrosisfree factor- alpha.}}</ref> Additionally, there are destablizingdestabilizing elements similar to SLDE found in [[Interleukin 2|IL-2]] and [[Interleukin 6|IL-6]]. The results of the study portrayed that the 3'-UTR of G-CSF mRNA contains a destablizingdestabilizing element that is insensitive to [[Calcium Ionophore A23187|calcium ionophore]], showing the importance ofhence SLDE in regulation ofregulates G-CSF mRNA. Also the study showed that AUDEs do not function in 5637 Bladder carinomacarcinoma cells, but the SLDE does. Lastly, the authors describe how the existence of theThe two destablizing elements, SLDE and AURE, providesprovide multiple mechanisms to confer flexibility ofregulate cytokine expression.
[[White blood cell|Leukocytes]] are important components in our [[Immune system|immune systems]] that include [[Neutrophil|neutrophils]]. Neutrophilss, are the most abundant type of granulocytes[[granulocyte]]s and are responsible for leading the majorityfirst response of the immune system response against invaders. Granulocyte-colony stimulating factor (G-CSF) is a [[glycoprotein]] that stimulates proliferation of neutrophil [[Progenitorprogenitor cell|progenitor cells]]s and leads to the maturation of neutrophils. [[Monocyte|Monocytesmonocyte]]s and [[Macrophage|macrophagesmacrophage]]s are the cells that secrete G-CSF, but it is found that [[Endothelium|endothelial cells]], [[Fibroblast|fibroblasts]], and [[Bone marrow|bone marrow stromal cells]] also secrete the glycoprotein. Expression of G-CSF glycoprotein is complex and has both transcription and post transcription regulation. Two specific types of [[Regulatory sequence|regulatory elements]] are present in the [[Three prime untranslated region|3' untranslated region]] (3'UTR) of G-CSF [[Messenger RNA|mRNA]]. These elements are referred to as adenylate uridylate-rich elements (AUREs) and stem-loop destabilizing element (SLDE). They have been shown to be destabilizing elements of the G-CSF mRNA. On the other hand, the stability of the mRNA is regulated by [[P38 mitogen-activated protein kinases|p38 mitogen-activated protein kinase]] (MAPK) and this phosphorylating enzyme has been shown to be linked to the AUREs in the 3'UTR. However, much is not known about the role p38 MAPK plays in the regulation of the stability of G-CSF mRNA.
ASB203580 studyspecifically publishedinhibits the [[Catalysis|catalytic activity]] of p38 MAPK by Shwu-Fencompetitively Changbinding etto the active site where [[ATP synthase|ATP]] is supposed to bind and is used to probe the role of p38 MAPK in cells.al<ref>{{Citecite journal |last vauthors = Chang|first=Shwu-Fen|last2= SF, Li|first2=Huai-Ci|last3= HC, Huang|first3=Yu-Pei|last4= YP, Tasi|first4=Wen-Ju|last5= WJ, Chou|first5=Yuan-Yi|last6= YY, Lu SC |first6=Shao-Chun|date=2016-12| title = SB203580 increases G-CSF production via a stem-loop destabilizing element in the 3’3' untranslated region in macrophages independently of its effect on p38 MAPK activity |url=http://www.jbiomedsci.com/content/23/1/3| journal = Journal of Biomedical Science |language=en| volume = 23 | issue = 1 | pages = 3 |doi=10.1186/s12929-016-0221-z|issn=1423-0127|pmc=PMC4715298|pmid=26772539}}</ref> investigateddate the= effectJanuary of2016 [[SB 203580|SB203580]], whichpmid is= a26772539 specific| inhibitorpmc of= p384715298 MAPK,| ondoi the= lipopolysaccharide10.1186/s12929-induced G016-CSF expression in macrophages at the [[Post0221-transcriptionalz regulation|post doi-transcription]]access level.= SB203580free specifically inhibits the [[Catalysis|catalytic activity]] of p38 MAPK by competitively binding to the active site where [[ATP synthase|ATP]] is supposed to bind and is widely used in other studies to display the role of p38 MAPK in other biological systems. Surprisingly, the results of the study showed that}}</ref> SB203580 amplified the lipopolysaccharide-induced increase in the G-CSF mRNA levels in mouse [[Bone marrow-derived macrophage|bone marrow-derived macrophages]] and in THP-1 human macrophages. By displaying that the decay of G-CSF mRNA, in the presence of [[Dactinomycin|actinomycin D]], was slower in SB203580-treated cells, it was shown. SB203580 increased the stability of G-CSF mRNA. Finally, by using experiments showing the effect of the 3’UTR of G-CSF on G-CSF stability, the SLDE was shown to beis essential for the SB203580-induced increase in the stability of mRNA.{{short description|RNA element}}
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