E2F-like elements in p27Kip1promoter specifically sense deregulated E2F activity

The transcription factor E2F, the main target of the RB tumor suppressor pathway, plays crucial roles not only in cell proliferation but also in tumor suppression. The cyclin-dependent kinase inhibitor p27(Kip1) gene, an upstream negative regulator of E2F, is induced by ectopically expressed E2F1 but not by normal growth stimulation that physiologically activates endogenous E2F. This suggests that the gene can discriminate between deregulated and physiological E2F activity. To address this issue, we examined regulation of the p27(Kip1) gene by E2F. Here we show that p27(Kip1) promoter specifically senses deregulated E2F activity through elements similar to typical E2F sites. This E2F-like elements were activated by deregulated E2F activity induced by forced inactivation of pRb but not by physiological E2F activity induced by serum stimulation, contrary to typical E2F sites activated by both E2F activity. The endogenous p27(Kip1) gene responded to deregulated and physiological E2F activity in the same manner to the E2F-like elements. Moreover, the E2F-like elements bound ectopically expressed E2F1 but not physiologically activated E2F1 or E2F4 in vivo. These results suggest that the p27(Kip1) gene specifically senses deregulated E2F activity through the E2F-like elements to suppress inappropriate cell cycle progression in response to loss of pRb function.