LAUSR

Diepoxybutane (DEB) is the most toxic metabolite of the environmental chemical 1,3‐butadiene. We previously demonstrated the occurrence of DEB‐induced p53‐mediated apoptosis in human lymphoblasts. The p53 protein functions as a master transcriptional regulator in orchestrating the genomic response to a variety of stress signals. Transcriptomic analysis indicated that C‐C chemokine ligand 4 (CCL4) gene expression was elevated in a p53‐dependent manner in DEB‐exposed p53‐proficient TK6 cells, but not in DEB‐exposed p53‐deficient NH32 cells. Thus, the objective of this study was to determine whether the CCL4 gene is a transcriptional target of p53 and deduce its role in DEB‐induced apoptosis in human lymphoblasts. Endogenous and exogenous wild‐type p53 transactivated the activity of the CCL4 promoter in DEB‐exposed lymphoblasts, but mutant p53 activity on this promoter was reduced by ∼80% under the same experimental conditions. Knockdown of the upregulated CCL4 mRNA levels in p53‐proficient TK6 cells inhibited DEB‐induced apoptosis by ∼45%–50%. Collectively, these observations demonstrate for the first time that the CCL4 gene is upregulated by wild‐type p53 at the transcriptional level, and this upregulation mediates apoptosis in DEB‐exposed human lymphoblasts.