p53 is an Important Regulator of CCL2 Gene Expression

Abstract

The p53 protein is a sequence-specific DNA-binding factor that regulates inflammatory genes such as CCL2/MCP-1 that may play a role in various diseases. A recent study has indicated that the knockdown of human p53 leads to a strong negative regulation of CCL2 induction. We are therefore interested in how p53 regulates CCL2 gene expression. In the following study, our findings indicate that UV-induced p53 accumulation in mouse macrophages significantly decreases LPS-induced CCL2 production, and that p53 binds to CCL2 5’UTR in the region (16-35). We also found that a p53 domain (p53pep170) mimics full length p53 to down-regulate CCL2 promoter activity. Treatment of p53-deficient mouse primary macrophages with synthetic p53pep170 was found to decrease LPS-induced production of CCL2 without association with cellular endogenous p53. CCL2 production induced by lentiCLG in human monocytes or mouse primary macrophages was blocked in the presence of p53pep170. Overall, these results demonstrate that p53 or its derived peptide (p53pep170) is an important regulator of CCL2 gene expression via its binding activity, and acts as a novel model for future studies linking p53 and its short peptide to pave the way to possible pharmaceutical intervention of CCL2-mediated inflammatory and cancer diseases.

p53 suppresses CCL2-induced subcutaneous tumor xenograft

“…However, it was found that p53 mutants lacking the C-terminal still bound to DNA and maintained significant transactivation and growth suppressor activity [38, 39]. Consistent with these studies, we reported a similar result: without its C-terminal, a short peptide of p53 alone is able to suppress the CCL2 gene expression via its binding activity [20]. …”

“…Additionally, a recent study has indicated that the knockdown of p53 leads to a strong negative regulation of CCL2 induction [20]. Therefore, we are interested in a model to test how p53 suppresses CCL2-mediated cancer disease.…”

Immune Surveillance of Unhealthy Cells by Natural Killer Cells

“…These data suggested a non-redundant role for p53-induced CCL2 expression in recruiting NK cells into senescent tumors in vivo. Published chromatin immunoprecipitation experiments show a direct association of p53 with the Ccl2 gene regulatory sequences consistent with the possibility that p53 directly transactivates Ccl2 (Hacke et al, 2010; Tang et al, 2012). Our new results suggested that induction of CCL2 production by p53 is a necessary event leading to the elimination of the senescent tumors by NK cells that recognize NKG2D ligands on the tumor cell surface (Figure 2).…”

Role of human pulmonary fibroblast-derived MCP-1 in cell activation and migration in experimental silicosis

“…Although mounting evidence suggests that the MCP-1/CCR2 axis is involved in fibrosis induced by SiO 2 , a recent study indicated that MCP-1 may exert an anti-fibrotic effect in a CCR2-independent manner (Kalderen et al, 2014). However, the concentration of MCP-1 that was exogenously administered in this study (1-60 nM, or 8.7-522 ng/mL) is much higher than that in most physiological and pathological conditions (0.005-1 ng/mL) (Zickus et al, 1998;Liao et al, 2010;Tang et al, 2012). In the current study, we observed that the level of MCP-1 released by fibroblasts was much lower than the dosage of MCP-1 that was exogenously administered.…”