G-CSF factor stem-loop destabilising element

Leukocytes are important components in our immune systems that include neutrophils. Neutrophils, are the most abundant type of granulocytes and are responsible for leading the majority of the immune system response against invaders. Granulocyte-colony stimulating factor (G-CSF) is a glycoprotein that stimulates proliferation of neutrophil progenitor cells and leads to the maturation of neutrophils. Monocytes and macrophages are the cells that secrete G-CSF, but it is found that endothelial cells, fibroblasts, and 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 elements are present in the 3' untranslated region (3'UTR) of G-CSF 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 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.                                    

A study published by Shwu-Fen Chang et.al investigated the effect of SB203580, which is a specific inhibitor of p38 MAPK, on the lipopolysaccharide-induced G-CSF expression in macrophages at the post-transcription level. SB203580 specifically inhibits the catalytic activity of p38 MAPK by competitively binding to the active site where 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 SB203580 amplified the lipopolysaccharide-induced increase in the G-CSF mRNA levels in mouse bone marrow-derived macrophages and in THP-1 human macrophages. By displaying that the decay of G-CSF mRNA, in the presence of 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 be essential for the SB203580-induced increase in the stability of mRNA.

G-CSF factor stem-loop destabilising element (SLDE)
Predicted secondary structure and sequence conservation of G-CSF_SLDE
Identifiers
Symbol	G-CSF_SLDE
Rfam	RF00183
Other data
RNA type	Cis-reg
Domain(s)	Eukaryota
SO	SO:0000233
PDB structures	PDBe

The G-CSF factor stem-loop destabilising element (SLDE) is an RNA element secreted by fibroblasts and endothelial cells in response to the inflammatory mediators interleukin-1 (IL-1) and tumour necrosis factor-alpha and by activated macrophages. The synthesis of G-CSF is regulated both 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 monocytes 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 poly(A) tail.

In another study by Cheryl Y Brown et.al showing the importance of the 3'UTR element SLDE of G-CSF mRNA is shown. AUREs are shown to be present in other cytokine mRNAs, but the SLDE is the most important element that stablizes G-CSF mRNA in response to IL-1 or tumor necrosis factor- alpha. Additionally, there are destablizing elements similar to SLDE found in IL-2 and IL-6. The results of the study portrayed that the 3'-UTR of G-CSF mRNA contains a destablizing element that is insensitive to calcium ionophore, showing the importance of SLDE in regulation of G-CSF mRNA. Also the study showed that AUDEs do not function in 5637 Bladder carinoma cells, but the SLDE does. Lastly, the authors describe how the existence of the two destablizing elements, SLDE and AURE, provides multiple mechanisms to confer flexibility of cytokine expression.

References

2.Chang, Shwu-Fen (16 January 2016). "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 of Biomedical Science. vol. 23, no. 3. doi:10.1186/s12929-016-0221-z. PMID 26772539 – via GALE ACADEMIC ONEFILE. {{cite journal}}: |volume= has extra text (help)CS1 maint: unflagged free DOI (link)

3. Brown, Cheryl Y (26 November 1996). "A Cytokine MRNA-Destabilizing Element That Is Structurally and Functionally Distinct from A + U-Rich Elements". Proceedings of the National Academy of Sciences of the United States of America. 93, no.24: 13721–13725. doi:10.1073/pnas.93.24.13721. PMID 8943001 – via JSTOR.

External links

• Page for G-CSF factor stem-loop destabilising element (SLDE) at Rfam