Murine Embryonic Stem Cells Possess Distinct E2F Activity That Activates Tumor Suppressor Promoter Elements

The transcription factor E2F plays crucial roles in cell proliferation and tumor suppression. In the resting state of normal cells, E2F activity is suppressed by binding of the tumor suppressor pRB and its family members. E2F activated by growth stimulation under the control of pRB (physiological E2F) activates growth-related genes and facilitates cell proliferation. In contrast, E2F activated by loss of pRB control, such as forced inactivation of pRB (distinct E2F), activates tumor suppressor genes such as ARF and TAp73 to suppress tumorigenesis. We previously reported that these genes are specifically activated by distinct E2F but not by physiological E2F. In almost all cancers, pRB function is disabled, generating distinct E2F activity, which is tolerated due to concomitant dysfunction of the tumor suppressor p53. Hence, distinct E2F activity is a characteristic feature of cancer cells. Mouse embryonic stem cells (mESCs) proliferate rapidly with shortened gap phases, enhanced cyclin dependent kinase (CDK) activity and hyper-phosphorylated (inactive) pRB. This observation prompted us to examine whether mESCs possess distinct E2F activity. We show here that, like cancer cell lines, mESCs exhibit distinct E2F activity. Moreover, introduction of a small amount of CDK inhibitors enhanced deregulated E2F activity, suggesting that it is suppressed by CDK activity in mESCs.