We identified Notch1 as a mediator of transcriptional repression of DR5. In line with our results, inhibition of Notch1 signaling pathway in breast cancer cells has recently been reported to increase the expression of DR4 and DR5 and to enhance the sensitivity to TRAIL-induced apoptosis.30 In contrast to these findings, activation of Notch1 signaling increased DR5 expression levels in a p53-dependent manner in hepatocellular carcinoma,31 pointing to a cell type dependent regulation. Here, TNFRSF10A is linked to hepatocellular carcinoma.