The p53 tumor suppressor protein, one of the most extensively studied proteins, plays a pivotal role in cellular checkpoints that respond to DNA damage to prevent tumorigenesis. However, the transcriptional control of the p53 gene has not been fully characterized. We report that the transcription factor E2F1 binds only to the E2F1 distal site of the p53 promoter in the human papillomavirus positive carcinoma HeLa cell line. Moreover, we showed that etoposide, a DNA damaging agent, activates p53 transcription through the E2F1 pathway. This increase correlates with apoptosis induction as disruption of this pathway led to reduced apoptosis stimulation by the DNA damaging agent.