Geminin Is Targeted for Repression by the Retinoblastoma Tumor Suppressor Pathway through Intragenic E2F Sites

摘要: The geminin protein is a critical regulator of DNA replication. It functions to control replication fidelity by blocking the assembly prereplication complexes in S and G(2) phases cell cycle. Geminin levels, which are low G(0)/G(1) increase at G(1)/S transition, controlled through coordinate transcriptional proteolytic regulation. Here we show that regulated transcriptionally retinoblastoma tumor suppressor (RB)/E2F pathway. Initially, observed activation RB led repression transcription. Conversely, Rb-null mouse embryonic fibroblasts have enhanced expression relative wild type fibroblasts. Similarly, an acute loss Rb adult deregulated RNA levels. To delineate responsible regulatory motifs, luciferase reporter constructs containing fragments promoter were generated. An analysis cis-acting elements indicated intragenic E2F sites down-stream first exon for RB-mediated geminin. direct endogenous revealed these occupied proteins, mutation eliminates responsiveness RB. Together, data link RB/E2F pathway represent this important