The retinoblastoma tumor suppressor protein pRB is conventionally regarded as an inhibitor of the E2F family of transcription factors. Conversely, pRB is also recognized as an activator of tissue-specific gene expression along various lineages including osteoblastogenesis. During osteoblast differentiation, pRB directly targets Alpl and Bglap, which encode the major markers of osteogenesis, alkaline phosphatase and osteocalcin. Surprisingly, p130 and repressor E2Fs were recently found to co-occupy and repress Alpl and Bglap in proliferating osteoblast precursors prior to differentiation. This raises the further question of whether these genes convert to E2F activation targets when differentiation begins, which would constitute a remarkable situation wherein pRB and E2F would be co-targeting genes for activation.Chromatin immunoprecipitation (ChIP) analysis in an osteoblast differentiation model shows Alpl and Bglap are indeed targeted by an activator E2F, i.e. E2F1. Promoter occupation of Alpl and Bglap by E2F1 occurs specifically during activation, and depletion of E2F1 severely impairs their induction. Mechanistically, promoter occupation by E2F1 and pRB is mutually dependent, and without this cooperative effect, activation steps previously shown to be dependent on pRB, including recruitment of RNA polymerase II, are impaired. Myocyte and adipocyte specific genes are also co-targeted by E2F1 and pRB during differentiation along their respective lineages. The finding that pRB and E2F1 cooperate to activate expression of tissue-specific genes is a paradigm distinct from the classical concept of pRB as an inhibitor of E2F1, but is consistent with the observed roles of these proteins in physiological models.
Citation Format: Stephen J. Flowers, Fuhua Xu, Elizabeth Moran. Cooperative activation of tissue specific genes by pRB and E2F1. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-115. doi:10.1158/1538-7445.AM2013-LB-115