title: Skp2 suppresses apoptosis in Rb1-deficient tumours by limiting E2F1 activity.
abstract: One mechanism of tumour suppression by pRb is repressing E2F1. Hence, E2f1 deletion diminishes tumorigenesis following Rb1 loss. However, E2F1 promotes both proliferation and apoptosis. It therefore remains unclear how de-repressed E2F1 promotes tumorigenesis. Another mechanism of pRb function is repressing Skp2 to elevate p27 to arrest proliferation. However, Skp2 deletion induced apoptosis, not proliferation arrest, in Rb1-deficient pituitary tumorigenesis. Here we show that Rb1 deletion induces higher expression of E2F1 target genes in the absence of Skp2. E2F1 binds less cyclin A but more target promoters when Rb1 is deleted with Skp2 knockout or p27T187A knockin, suggesting that stabilized p27 prevents cyclin A from binding and inhibiting E2F1. In Rb1-deficient pituitary tumorigenesis, Skp2 deletion or p27T187A mutation converts E2F1's role from proliferative to apoptotic. These findings delineate a pRb-Skp2-p27-cyclin A-E2F1 pathway that determines whether E2F1 is proliferative or apoptotic in Rb1-deficient tumorigenesis.
authors.affiliation: Department of Developmental and Molecular Biology and Ophthalmology and Visual Sciences and Medicine, The Albert Einstein Comprehensive Cancer Center and Liver Research Center, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
authors.forename: Zhonglei
authors.initials: Z
authors.lastname: Lu
authors.affiliation: Department of Developmental and Molecular Biology and Ophthalmology and Visual Sciences and Medicine, The Albert Einstein Comprehensive Cancer Center and Liver Research Center, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
authors.forename: Frederick
authors.initials: F
authors.lastname: Bauzon
authors.affiliation: Department of Developmental and Molecular Biology and Ophthalmology and Visual Sciences and Medicine, The Albert Einstein Comprehensive Cancer Center and Liver Research Center, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
authors.forename: Hao
authors.initials: H
authors.lastname: Fu
authors.affiliation: Department of Developmental and Molecular Biology and Ophthalmology and Visual Sciences and Medicine, The Albert Einstein Comprehensive Cancer Center and Liver Research Center, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
authors.forename: Jinhua
authors.initials: J
authors.lastname: Cui
authors.affiliation: Department of Developmental and Molecular Biology and Ophthalmology and Visual Sciences and Medicine, The Albert Einstein Comprehensive Cancer Center and Liver Research Center, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
authors.forename: Hongling
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Division of Cell Proliferation, ART, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Nakayama
authors.affiliation: Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Keiich I
authors.initials: KI
authors.lastname: Nakayama
authors.affiliation: Department of Developmental and Molecular Biology and Ophthalmology and Visual Sciences and Medicine, The Albert Einstein Comprehensive Cancer Center and Liver Research Center, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
authors.forename: Liang
authors.initials: L
authors.lastname: Zhu
mesh_terms: D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D015536:Down-Regulation; D050687:E2F1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D018345:Mice, Knockout; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology; D010902:Pituitary Gland / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000172:deficiency* / Q000235:genetics; D044786:S-Phase Kinase-Associated Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D050687:E2F1 Transcription Factor; C493754:E2f1 protein, mouse; D016160:Retinoblastoma Protein; D044786:S-Phase Kinase-Associated Proteins