The G-CSF factor stem-loop destabilising element (SLDE) is an RNA element secreted by

fibroblast A fibroblast is a type of cell (biology), biological cell that synthesizes the extracellular matrix and collagen, produces the structural framework (Stroma (tissue), stroma) for animal Tissue (biology), tissues, and plays a critical role in wound ...

s and

endothelial cells The endothelium is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the rest of the vessel ...

in response to the inflammatory mediators

interleukin-1 The Interleukin-1 family (IL-1 family) is a group of 11 cytokines that plays a central role in the regulation of immune and inflammatory responses to infections or sterile insults. Discovery Discovery of these cytokines began with studies on t ...

(IL-1) and

tumour necrosis factor-alpha Tumor necrosis factor (TNF, cachexin, or cachectin; formerly known as tumor necrosis factor alpha or TNF-α) is an adipokine and a cytokine. TNF is a member of the TNF superfamily, which consists of various transmembrane proteins with a homolog ...

and by activated

macrophage Macrophages (abbreviated as M φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer cel ...

s. The synthesis of G-CSF is regulated both transcriptionally and through control of

mRNA In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of Protein biosynthesis, synthesizing a protein. mRNA is ...

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 Monocytes are a type of leukocyte or white blood cell. They are the largest type of leukocyte in blood and can differentiate into macrophages and conventional dendritic cells. As a part of the vertebrate innate immune system monocytes also inf ...

s and macrophages, in response to

lipopolysaccharide Lipopolysaccharides (LPS) are large molecules consisting of a lipid and a polysaccharide that are bacterial toxins. They are composed of an O-antigen, an outer core, and an inner core all joined by a covalent bond, and are found in the outer m ...

. 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 Polyadenylation is the addition of a poly(A) tail to an RNA transcript, typically a messenger RNA (mRNA). The poly(A) tail consists of multiple adenosine monophosphates; in other words, it is a stretch of RNA that has only adenine bases. In euk ...

. Adenylate uridylate-rich elements (AUREs) are present in 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. Additionally, there are destabilizing elements similar to SLDE found in

IL-2 The Ilyushin Il-2 (Russian language, Russian: Илью́шин Ил-2) is a Ground attack aircraft, ground-attack plane that was produced by the Soviet Union in large numbers during the World War II, Second World War. The word ''shturmovík'' (C ...

and IL-6. The 3'-UTR of G-CSF mRNA contains a destablizing element that is insensitive to calcium ionophore, hence SLDE regulates G-CSF mRNA. AUDEs do not function in 5637 Bladder carcinoma cells, but the SLDE does. The two destablizing elements, SLDE and AURE, provide multiple mechanisms to regulate cytokine expression.

Neutrophil Neutrophils (also known as neutrocytes or heterophils) are the most abundant type of granulocytes and make up 40% to 70% of all white blood cells in humans. They form an essential part of the innate immune system, with their functions varying in ...

s, are the most abundant type of

granulocyte Granulocytes are cells in the innate immune system characterized by the presence of specific granules in their cytoplasm. Such granules distinguish them from the various agranulocytes. All myeloblastic granulocytes are polymorphonuclear. They ha ...

s and are responsible for leading the first response of the immune system response against invaders. Granulocyte-colony stimulating factor (G-CSF) is a

glycoprotein Glycoproteins are proteins which contain oligosaccharide chains covalently attached to amino acid side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycos ...

that stimulates proliferation of neutrophil

progenitor cell A progenitor cell is a Cell (biology), biological cell that can Cellular differentiation, differentiate into a specific cell type. Stem cells and progenitor cells have this ability in common. However, stem cells are less specified than progenitor ...

s and leads to the maturation of neutrophils.

s and

s are the cells that secrete G-CSF, but it is found that

fibroblasts A fibroblast is a type of biological cell that synthesizes the extracellular matrix and collagen, produces the structural framework ( stroma) for animal tissues, and plays a critical role in wound healing. Fibroblasts are the most common cells o ...

, and

bone marrow stromal cells Bone marrow is a semi-solid tissue found within the spongy (also known as cancellous) portions of bones. In birds and mammals, bone marrow is the primary site of new blood cell production (or haematopoiesis). It is composed of hematopoietic ce ...

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 A regulatory sequence is a segment of a nucleic acid molecule which is capable of increasing or decreasing the expression of specific genes within an organism. Regulation of gene expression is an essential feature of all living organisms and vir ...

are present in the

3' untranslated region In molecular genetics, the three prime untranslated region (3′-UTR) is the section of messenger RNA (mRNA) that immediately follows the translation termination codon. The 3′-UTR often contains regulatory regions that post-transcriptionally ...

(3'UTR) of G-CSF

. 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 p38 mitogen-activated protein kinases are a class of mitogen-activated protein kinases (MAPKs) that are responsive to stress stimuli, such as cytokines, ultraviolet irradiation, heat shock, and osmotic shock, and are involved in cell different ...

(MAPK) and this phosphorylating enzyme has been shown to be linked to the AUREs in the 3'UTR. SB203580 specifically inhibits the

catalytic activity Catalysis () is the process of increasing the rate of a chemical reaction by adding a substance known as a catalyst (). Catalysts are not consumed in the reaction and remain unchanged after it. If the reaction is rapid and the catalyst recyc ...

of p38 MAPK by competitively binding to the active site where ATP is supposed to bind and is used to probe the role of p38 MAPK in cells. 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 Dactinomycin, also known as actinomycin D, is a chemotherapy medication used to treat a number of types of cancer. This includes Wilms tumor, rhabdomyosarcoma, Ewing's sarcoma, trophoblastic neoplasm, testicular cancer, and certain types of ovari ...

, was slower in SB203580-treated cells. SB203580 increased the stability of G-CSF mRNA. SLDE is essential for the SB203580-induced increase in the stability of mRNA.

References

External links

* Cis-regulatory RNA elements {{molecular-cell-biology-stub