The transcription factor p73 is a structural homologue of p53 and plays an important role in tumorigenesis, differentiation and development. However, the regulation of p73 pathway has not been wholly understood. Here we reported that YY1-silencing resulted in significant reductions in the activities of the p73 promoters and the endogenous p73 expression level, conversely, overexpression of YY1 could induce the activities of them. Furthermore, we showed that YY1 and E2F1 have synergistic effect on p73 promoter activity. The results of YY1-silencing and E2F1-silencing alone revealed that both factors are involved in the doxorubicin-induced activation of p73 promoter. Immunofluorescence staining and co-immunoprecipitation assays demonstrated that cooperation of YY1 and E2F1 is concomitant with physical interaction in nuclei. The results presented here suggested the cooperative transcriptional regulation of p73 by YY1 and E2171, and might provide a new regulation mechanism by the YY1 network on tumorigenesis, differentiation and development. (c) 2007 Elsevier Inc. All rights reserved.