CXCL1: Gene, Promoter, Regulation of Expression, mRNA Stability, Regulation of Activity in the Intercellular Space

Abstract

CXCL1 is one of the most important chemokines, part of a group of chemotactic cytokines involved in the development of many inflammatory diseases. It activates CXCR2 and, at high levels, CXCR1. The expression of CXCL1 is elevated in inflammatory reactions and also has important functions in physiology, including the induction of angiogenesis and recruitment of neutrophils. Due to a lack of reviews that precisely describe the regulation of CXCL1 expression and function, in this paper, we present the mechanisms of CXCL1 expression regulation with a special focus on cancer. We concentrate on the regulation of CXCL1 expression through the regulation of CXCL1 transcription and mRNA stability, including the involvement of NF-κB, p53, the effect of miRNAs and cytokines such as IFN-γ, IL-1β, IL-17, TGF-β and TNF-α. We also describe the mechanisms regulating CXCL1 activity in the extracellular space, including proteolytic processing, CXCL1 dimerization and the influence of the ACKR1/DARC receptor on CXCL1 localization. Finally, we explain the role of CXCL1 in cancer and possible therapeutic approaches directed against this chemokine.

Keywords: CXCL1; CXCR2; Gro-α; MGSA; cancer; chemokine; inflammation; neutrophil; tumor.

Figure 1

Factors affecting CXCL1 gene transcription. The CXCL1 promoter contains binding sites for factors that bind to these sites. They either increase (shown in red) or decrease (shown in blue) CXCL1 expression. In particular, the CXCL1 promoter contains a binding site for STAT1 and Sp1. STAT1 and Sp1 activated by IFN-γ and TNF-α, respectively, attach to these sites. Sp1 increases CXCL1 expression; however, STAT1 inhibits Sp1 binding to the CXCL1 promoter. Another mechanism regulating CXCL1 expression is IUR, a region that directly borders the NF-κB binding site. CDP binds to IUR, which inhibits the recruitment of CBP and PCAF coactivators by NF-κB. This prevents the induction of CXCL1 expression by NF-κB.

Figure 2

Effect of microRNAs on CXCL1 expression in a tumor. In cancer tumors, CXCL1 expression is regulated by microRNAs. Based on the available literature, six different microRNAs that decrease CXCL1 expression have been identified to date.

Figure 3

Structure of CXCL1. The tertiary structure of CXCL1 with the two disulfide bridges is highlighted in yellow. The N-terminal structure of CXCL1 is not stabilized; therefore, the figure shows many different possible conformations of this, as well as the other terminus of the CXCL1 chain. The graphic was created using RasMol 2.7.4.2 [136,137], and the CXCL1 structure was deposited in the Protein Data Bank (PDB) [138] under the identifier 1MGS [133,134].