Abstract
ObjectiveTo determine the mechanism by which CDKN1C binds and transcriptionally represses E2F1‐driven transcription. We previously found that E2F1 can induce transcription of the cyclin‐dependent kinase inhibitor CDKN1C (p57, KIP2). Furthermore, we showed that the CDKN1C protein could in turn repress E2F1‐driven transcription. In the current work, we explore the mechanism by which CDKN1C represses E2F1‐driven transcription. We demonstrate that E2F1 and CDKN1C can form stable complexes both in vivo and in vitro. Molecular studies demonstrate that the E2F1/CDKN1C interaction is mediated by two E2F domains. A central E2F1 region containing the "marked box" domain interacts directly with CDKN1C, whereas a C‐terminal E2F1 domain interacts with CDKN1C via interaction with Rb. Chromatin immunoprecipation assays demonstrate that CDKN1C associates with known E2F1‐regulated promoters in vivo. Overexpression of CDKN1C results in an inhibition of RNA polymerase II C‐terminal domain phosphorylation suggesting a mechanism by which promoter‐associated CDKN1C may inhibit transcription. These results highlight a novel mechanism by which E2F1 transcriptional activity is restrained.
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