p53 is an important regulator of CCL2 gene expression.
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.
Center for Anti- Inflammatory Therapeutics, Boston University, 650 Albany Street, X- 343, Boston, MA 02118, USA. xrtang@bu.edu
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Tang
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Asano
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O'Reilly
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Farquhar
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Yang
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Amar
D020121:5' Untranslated Regions; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D045744:Cell Line, Tumor; D018932:Chemokine CCL2 / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008156:Luciferases / Q000096:biosynthesis / Q000235:genetics; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000528:radiation effects; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000378:metabolism / Q000502:physiology; D011401:Promoter Regions, Genetic; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism / Q000502:physiology*
D020121:5' Untranslated Regions; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D018836:Inflammation Mediators; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D010446:Peptide Fragments; D016159:Tumor Suppressor Protein p53; D008156:Luciferases