9821

RB1CC1

ATG17|CC1|FIP200|PPP1R131;RB1-inducible coiled-coil 1;RB1CC1;RB1-inducible coiled-coil 1

200 kDa FAK family kinase-interacting protein|FAK family kinase-interacting protein of 200 kDa|RB1-inducible coiled-coil protein 1|phosphatase 1, regulatory subunit 131

8q11

protein-coding

RB1-inducible coiled-coil 1 (RB1CC1) is a novel tumor suppressor implicated in the regulation of RB1 expression. It is abundant in post-mitotic neuromuscular cells, which are matured and enlarged, but scarce in smaller leukocytes, indicating an association between RB1CC1 status and cell size. To clarify whether RB1CC1 is involved in cell size control, we investigated the contribution of RB1CC1 to the TSC-mTOR pathway, which plays an important role in the control through translational regulation. RNAi-mediated knockdown of RB1CC1 reduced the activation of mTOR and S6K as well as the size of HEK293 and C2C12 cells. Such knockdown also suppressed RB1 expression and the population of G1-phase cells. Exogenous expression of RB1CC1 maintained S6K activity and cell size, and decreased TSC1/hamartin contents under nutritionally starved conditions, which usually inhibit the mTOR-S6K pathway. Furthermore, RB1CC1 interfered with and degraded TSC1 through the ubiquitin-proteasomal pathway. A lentiviral RNAi for RB1CC1 reduced the size of mouse leg muscles. These findings suggest that RB1CC1 is required to maintain both RB1 expression and mTOR activity. The activity of mTOR was supported by RB1CC1 through TSC1 degradation. RB1CC1 preserved cell size without cell cycle progression especially in neuromuscular tissues, and the abundance contributed to the non-proliferating enlarged cell phenotype.

RB1-inducible coiled-coil 1 (RB1CC1, also known as FIP200) is a tumor suppressor implicated in the regulation of RB1 (retinoblastoma 1) expression. However, the molecular mechanism of RB1 regulation by RB1CC1 has not been elucidated. Here, we demonstrate that nuclear RB1CC1 binds to the RB1 promoter using chromatin immunoprecipitation assays with anti-RB1CC1 antibody. Luciferase assays with RB1 promoter reporter plasmids revealed that RB1CC1 activated the RB1 promoter through the 201 bp upstream GC-rich region (from the initiation ATG). Electrophoretic mobility shift assay and Western blot analysis supported RB1CC1 binding to the GC-rich region of the RB1 promoter. In addition, the C-terminus of RB1CC1 was required for nuclear localization and subsequent RB1 promoter activation. Furthermore, the expression levels of RB1CC1 and RB1 significantly correlated with in vivo breast cancer tissues as determined by immunohistochemical analysis. These data indicate that nuclear RB1CC1 directly activates the RB1 promoter to enhance RB1 expression in cancer cells. Evaluation of RB1CC1 in various types of human cancer tissues is expected to provide useful information for clinical practice and future therapeutic strategies.