Fine Tuning the Transcriptional Regulation of the CXCL1 Chemokine

Abstract

Constitutive activation of the transcription factor nuclear factor-κB (NF-κB) plays a major role in inflammatory diseases as well as cancer by inducing the endogenous expression of many proinflammatory proteins such as chemokines, and facilitating escape from apoptosis. The constitutive expression of chemokines such as CXCL1 has been correlated with growth, angiogenesis, and metastasis of cancers such as melanoma. The transcription of CXCL1 is regulated through interactions of NF-κB with other transcriptional regulatory molecules such as poly(ADP-ribose) polymerase-1 (PARP-1) and cAMP response element binding protein (CREB)-binding protein (CBP). It has been proposed that these two proteins interact with NF-κB and other enhancers to form an enhanceosome at the promoter region of CXCL1 and modulate CXCL1 transcription. In addition to these positive cofactors, a negative regulator, CAAT displacement protein (CDP), may also be involved in the transcriptional regulation of CXCL1. It has been postulated that the elevated expression of CXCL1 in melanomas is due to altered interaction between these molecules. CDP interaction with the promoter down-regulates transcription, whereas PARP and/or CBP interactions enhance transcription. Thus, elucidation of the interplay between components of the enhanceosome of this gene is important in finding more efficient and new therapies for conditions such as cancer as well as acute and chronic inflammatory diseases. I. Chemotactic CytokinesChemokines are small, proinflammatory, inducible, secreted cytokines that are involved in trafficking, activation, and proliferation of many cell types such as myeloid, lymphoid, pigment epidermal, and endothelial cells (1). Chemokine proteins are encoded by 70-130 amino acids, which also include a signal peptide sequence of 20-25 amino acids. It is interesting to note that although chemokines share little homology in their primary sequence, their overall tertiary structure is similar (2). Chemokines have been observed to form dimers in concentrated solutions and on crystallization, however, these concentrations are much higher than the biological concentrations. It is now commonly accepted that chemokines act as monomers in biological systems (2-4). To date, over 50 chemokines have been identified and assigned to four classes according to their arrangement of the first two of four conserved cysteine residues: C, CC, CXC, and CX 3 C chemokines (Table I). The C chemokines such as lymphotactin (XCL1) lack two of the four conserved cysteine residues, whereas CC chemokines have the first two cysteines adjacent to each other; examples are chemoattractant protein-1 (CCL2), macrophage inflammatory protein-1α (CCL3), and Copyright 2003, Elsevier (USA). All rights reserved. NIH Public Access Author ManuscriptProg Nucleic Acid Res Mol Biol. Author manuscript; available in PMC 2011 July 20. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript regulated upon activation of normal T cells expressed and secreted (CCL5). In CX 3 C ch...

A CXCL1 Paracrine Network Links Cancer Chemoresistance and Metastasis

“…CXCL1/2 are target genes of the NFκB/STAT1 pathway (Amiri and Richmond, 2003). Among a panel of prototypical activators of the NFκB/STAT1 pathway that we assayed by qRT-PCR, TNF -α was strikingly induced in endothelial cells upon doxorubicin chemotherapy treatment (Figure 6B).…”

Growth of Triple-Negative Breast Cancer Cells Relies upon Coordinate Autocrine Expression of the Proinflammatory Cytokines IL-6 and IL-8

“…These genes share several critical transcription factor binding sites in their proximal promoters, including AP-1, NF-κB and C/EBP binding sites (32-36). Therefore, to determine which transcription factors were induced by LPA stimulation, we measured luciferase activity of transcription factor-specific reporters in serum-starved TNBCs ( Figure 3D ).…”

A type I IFN-dependent DNA damage response regulates the genetic program and inflammasome activation in macrophages

“…Thus, it is possible that DDR in activated macrophages regulate chemokine gene expression by augmenting NF-κB activation. Moreover, Cxcl1 expression is regulated by NF-κB and poly(ADP-ribose) polymerase (PARP)−1, which is activated by DNA damage and has a broad range of functions in DDR (Amiri and Richmond, 2003; Nirodi et al, 2001; Rouleau et al, 2010). Thus, in activated macrophages, the initiation of a DDR may regulate the genetic program through multiple signaling and transcription pathways.…”