ATF5 transcription factor plays an essential role in hematopoietic and glioma cell survival and neuronal cell differentiation. Here, we report for the first time the pro-apoptosis role of ATF5 and identify Cyclin D3 as an ATF5-targeted apoptosis-related gene. The ectopic expression of ATF5 in HeLa cells could markedly increase cisplatin-induced apoptosis and the cleavage of Caspase-3, and induce Cyclin D3 mRNA expression via cooperation with E2F1 transcription factor. Moreover, the interference of Cyclin D3 expression by transfection with Cyclin D3 RNAi could protect cells from ATF5-mediated apoptosis induced by cisplatin, indicating the contribution of Cyclin D3 in ATF5-mediated apoptosis. Taken together, these results suggest that ATF5 increases cisplatin-induced apoptosis through up-regulation of Cyclin D3 transcription, which elicits survival signals ill HeLa cells. (c) 2005 Elsevier Inc. All rights reserved.