|
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>
[[AU-rich element|Adenylate uridylate-rich elements]] (AUREs) are present in other cytokine mRNAs, but the SLDE is the most important element that stablizesstabilizes G-CSF mRNA in response to IL-1 or tumor necrosis factor- alpha.<ref>{{cite journal | vauthors = Brown CY, Lagnado CA, Goodall GJ | title = A cytokine mRNA-destabilizing element that is structurally and functionally distinct from A+U-rich elements | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 93 | issue = 24 | pages = 13721–13725 | date = November 1996 | pmid = 8943001 | pmc = 19403 | doi = 10.1073/pnas.93.24.13721 | bibcode = 1996PNAS...9313721B | doi-access = free }}</ref> Additionally, there are destablizingdestabilizing elements similar to SLDE found in [[Interleukin 2|IL-2]] and [[Interleukin 6|IL-6]]. The 3'-UTR of G-CSF mRNA contains a destablizingdestabilizing element that is insensitive to [[Calcium Ionophore A23187|calcium ionophore]], hence SLDE regulates G-CSF mRNA. AUDEs do not function in 5637 Bladder carinomacarcinoma cells, but the SLDE does. The two destablizing elements, SLDE and AURE, provide multiple mechanisms tito regulate 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.
SB203580 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 displayprobe the role of p38 MAPK in other biological systemscells.<ref>{{cite journal | vauthors = Chang SF, Li HC, Huang YP, Tasi WJ, Chou YY, Lu SC | title = SB203580 increases G-CSF production via a stem-loop destabilizing element in the 3' untranslated region in macrophages independently of its effect on p38 MAPK activity | journal = Journal of Biomedical Science | volume = 23 | issue = 1 | pages = 3 | date = January 2016 | pmid = 26772539 | pmc = 4715298 | doi = 10.1186/s12929-016-0221-z | doi-access = free }}</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. SLDE is essential for the SB203580-induced increase in the stability of mRNA.{{short description|RNA element}}
== References ==
|
