Abstract
RB1-inducible coiled-coil 1 (RB1CC1, also known as FIP200) plays a role in the enhancement of the RB1 pathway through the direct binding to a GC-rich region 201bp upstream (from the initiation ATG) of the RB1 promoter. Here, we identified hSNF5 and p53 as the binding partners of RB1CC1 by immunoprecipitation and immunofluorescence assays. Interaction between these molecules and the RB1 pathway was analyzed by the assays of chromatin immunoprecipitation, luciferase-reporter, reverse transcription-polymerase chain reaction and immunoblot. The tumor growth suppression by RB1CC1 was evaluated by flow cytometry or by a cell growth assay. The nuclear RB1CC1 complex involving hSNF5 and/or p53 activated transcription of RB1, p16 and p21, and suppressed tumor cell growth. Furthermore, nuclear RB1CC1 expression significantly correlated with those of RB1 and p16 in breast cancer tissue in vivo, and the Ki-67 proliferation index was dependent on p53 as well as RB1CC1. The present study indicates that RB1CC1 together with hSNF5 and/or p53 enhances the RB1 pathway through transcriptional activation of RB1, p16 and p21. Evaluation of RB1CC1 expression combined with RB1 and p53 status is expected to provide useful information in clinical practice and future therapeutic strategies in breast cancer.
Highlights
The retinoblastoma tumor suppressor protein (RB1) regulates G1/S-phase cell cycle progression and is a critical mediator of antiproliferative signaling
RB1inducible coiled-coil 1 (RB1CC1) forms a complex with hSNF5 and/or p53 We initially attempted to identify RB1CC1-binding proteins in MCF-7 breast cancer cells by an immunoprecipitation assay followed by liquid chromatography-tandem mass spectrometry (LC-MS/MS)
RB1CC1 is a novel regulator of RB1 that dephosphorylates RB1 [2,6] and increases its expression [2,4]; in addition, a genetic rearrangement of RB1CC1 might be involved in breast cancer tumorigenesis [3,5]
Summary
The retinoblastoma tumor suppressor protein (RB1) regulates G1/S-phase cell cycle progression and is a critical mediator of antiproliferative signaling. RB1inducible coiled-coil 1 (RB1CC1: the symbol used here, which is approved by the Human Genome Organization [HUGO] Gene Nomenclature Committee; it is known as FIP200, focal adhesion kinase family-interacting protein of 200 kDa) was identified as an RB1 pathway regulator that in particular enhances RB1 transcription [2,3]. We have demonstrated that nuclear RB1CC1 binds to a GC-rich region 201bp upstream (from the initiation ATG) of the RB1 promoter and activates the expression of RB1 [4]. It has been reported that RB1CC1 binds and stabilizes p53 [6], suggesting that RB1CC1 might be an important mediator connecting the RB1 and p53 pathways. Nuclear RB1CC1 significantly correlates RB1 and p16 expression in breast cancer tissue in vivo
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