Mouse DDA3 (mDDA3) is a microtubule-associated protein that promotes cell growth. mDDA3 contains an intronic p53 binding motif that is absent in human DDA3 (hDDA3), and is transcriptionally activated during DNA damage in a p53-dependent way. We now report that hDDA3 mRNA and protein levels were suppressed by p53, as well as in DNA damaged cells harboring wild type, but not mutant-p53 expression. We have located three consensus El-Deiry decamers at -1478/-1403 of the hDDA3 gene, and shown by chromatin immunoprecipitation that p53 bound to the region. Luciferase analysis showed that the hDDA3 promoter containing the putative p53 binding motif was responsible for p53-mediated repression. Expression of hDDA3 decreased the cell's requirement for serum, furthermore, overexpression of hDDA3 mRNA was detected in hepatoma tissues. Together our results show that hDDA3 is a p53- and DNA-damage down-regulated target that exhibits oncogenic characteristics. (C) 2008 Elsevier Inc. All rights reserved.