The E2F-1 transcription factor is a critical downstream target of the tumor suppressor, RB. When activated, E2F-1 induces cell proliferation. In addition, deregulation of E2F-1 constitutes an oncogenic stress that can induce apoptosis. The protein kinase ATM is a pivotal mediator of the response to another type of stress, genotoxic stress. In response to ionizing radiation, ATM activates the tumor suppressor p53, a key player in the control of cell growth and viability. We show here that E2F-1 elevates ATM promoter activity and induces an increase in ATM mRNA and protein levels. This is accompanied by an E2F-induced increase in p53 phosphorylation. Expression of the E7 protein of HPV16, which dissociates RB/E2F complexes, also induces the elevation of ATM levels and p53 phosphorylation, implicating endogenous E2F in these phenomena. These data demonstrate that ATM is transcriptionally regulated by E2F-1 and suggest that ATM serves as a novel, ARF-independent functional link between the RB/E2F pathway and p53.
Bibliographical noteFunding Information:
We thank Dr Moshe Oren for pBABE-E7 and pBABE-E7D (21–35) and anti-p53 antibodies, Dr Yossi Shiloh for anti-ATM antibodies, Dr Kristian Helin for pBABE-HA-ER-E2F-1 and Dr Reuven Agami for pRetroSuper-p53siRNA. We are indebted to Drs Shiloh and Oren for discussions and a critical reading of this manuscript. This study was supported by the Israel Cancer Research Fund (ICRF) and Yad Abraham Research Center for Diagnostics and Therapy. DG is an incumbent of the Recanati Career Development chair of cancer research.
- Oncogenic stress