Tandem E2F Binding Sites in the Promoter of the p107 Cell Cycle Regulator Control p107 Expression and Its Cellular Functions

• DOI: 10.1371/journal.pgen.1001003
• Publication Date: 2010-06-24T20:25:06Z
• Authors: Deborah L. Burkhart; Stacey E. Wirt; Anne-Flore Zmoos; Michael S. Kareta; Julien Sage
• Keywords: E2F; Retinoblastoma protein; Chromatin immunoprecipitation

The retinoblastoma tumor suppressor (Rb) is a potent and ubiquitously expressed cell cycle regulator, but patients with germline Rb mutation develop very specific spectrum. This surprising observation raises the possibility that mechanisms compensate for loss of function are present or activated in many types. In particular, p107, protein related to Rb, has been shown functionally overlap several cellular contexts. To investigate underlying this functional redundancy between p107 vivo, we used gene targeting embryonic stem cells engineer point mutations two consensus E2F binding sites endogenous promoter. Analysis normal mutant by expression chromatin immunoprecipitation assays showed members families directly bound these sites. Furthermore, found controlled both repression quiescent also its activation cycling cells, as well cells. Cell further indicated transcription during S phase through was critical progression, uncovering role slow proliferation mammalian Direct transcriptional family provides molecular mechanism negative feedback loop progression tumorigenesis. These experiments suggest novel therapeutic strategies increase levels