Identification of DMP1 as Novel p53 Repressed Transcriptional Target.

The transcription factor DMP1 is a positive regulator of the tumor suppressor ARF, which in turn controls cell-cycle progression and/or apoptosis through p53. Given the role of DMP1 in the ARF-p53 pathway, we investigated whether the p53 transcription factor might regulate DMP1 expression. We found that endogenous human (h)DMP1 mRNA levels were significantly decreased upon induction of the temperature-sensitive p53Val135 in normal fibroblasts. Consistent with this observation, a p53 knockdown in MCF7 breast cancer cells resulted in increased hDMP1 mRNA and protein levels. At the molecular level, we found that p53 directly repressed the hDMP1 promoter activity by up to 90%. This repression was not mediated by p53 binding to the two putative p53-binding sites in the hDMP1 promoter. Instead, deletion analysis revealed a 300bp region containing an EGR1/SP1 binding site that is required for p53-dependent inhibition of hDMP1 promoter activity. Using Sp1-deficient SL2 insect cells, we confirmed that p53-mediated repression of hDMP1 is dependent on Sp1. Furthermore, chromatin immunoprecipitation demonstrated SP1 binding to the hDMP1 promoter. Together, our findings identify an Sp1-dependent, p53-mediated repression of DMP1.