title: A Novel Retinoblastoma Protein (RB) E3 Ubiquitin Ligase (NRBE3) Promotes RB Degradation and Is Transcriptionally Regulated by E2F1 Transcription Factor.
abstract: Retinoblastoma protein (RB) plays critical roles in tumor suppression and is degraded through the proteasomal pathway. However, E3 ubiquitin ligases responsible for proteasome-mediated degradation of RB are largely unknown. Here we characterize a novel RB E3 ubiquitin ligase (NRBE3) that binds RB and promotes RB degradation. NRBE3 contains an LXCXE motif and bound RB in vitro. NRBE3 interacted with RB in cells when proteasome activity was inhibited. NRBE3 promoted RB ubiquitination and degradation via the ubiquitin-proteasome pathway. Importantly, purified NRBE3 ubiquitinated recombinant RB in vitro, and a U-box was identified as essential for its E3 activity. Surprisingly, NRBE3 was transcriptionally activated by E2F1/DP1. Consequently, NRBE3 affected the cell cycle by promoting G1/S transition. Moreover, NRBE3 was up-regulated in breast cancer tissues. Taken together, we identified NRBE3 as a novel ubiquitin E3 ligase for RB that might play a role as a potential oncoprotein in human cancers.
authors.affiliation: Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education); Genetics Laboratory, Peking University School of Oncology, Beijing Cancer Hospital and Institute, Beijing 100142, China.
authors.forename: Yingshuang
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education); Genetics Laboratory, Peking University School of Oncology, Beijing Cancer Hospital and Institute, Beijing 100142, China.
authors.forename: Zongfang
authors.initials: Z
authors.lastname: Zheng
authors.affiliation: Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education).
authors.forename: Jingyi
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education); Genetics Laboratory, Peking University School of Oncology, Beijing Cancer Hospital and Institute, Beijing 100142, China.
authors.forename: You
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education); Genetics Laboratory, Peking University School of Oncology, Beijing Cancer Hospital and Institute, Beijing 100142, China.
authors.forename: Ruirui
authors.initials: R
authors.lastname: Kong
authors.affiliation: Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education); Genetics Laboratory, Peking University School of Oncology, Beijing Cancer Hospital and Institute, Beijing 100142, China.
authors.forename: Jiangying
authors.initials: J
authors.lastname: Liu
authors.affiliation: Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education); Genetics Laboratory, Peking University School of Oncology, Beijing Cancer Hospital and Institute, Beijing 100142, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education); Department of Cell Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Hongkui
authors.initials: H
authors.lastname: Deng
authors.affiliation: Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education); Department of Cell Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China. Electronic address: duxiaojuan100@bjmu.edu.cn.
authors.forename: Xiaojuan
authors.initials: X
authors.lastname: Du
authors.affiliation: Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education); Genetics Laboratory, Peking University School of Oncology, Beijing Cancer Hospital and Institute, Beijing 100142, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Ke
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D001943:Breast Neoplasms / Q000503:physiopathology; D045744:Cell Line, Tumor; D004247:DNA; D050687:E2F1 Transcription Factor / Q000502:physiology*; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D059748:Proteolysis; D056286:Retinoblastoma Binding Proteins; D016160:Retinoblastoma Protein / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D014158:Transcription, Genetic / Q000502:physiology*; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry / Q000502:physiology*; D015854:Up-Regulation
chemical_list: D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; C000606393:RB1 protein, human; D056286:Retinoblastoma Binding Proteins; D016160:Retinoblastoma Protein; D004247:DNA; D044767:Ubiquitin-Protein Ligases
keywords: E2F transcription factor; E3 ubiquitin ligase; cell cycle; protein degradation; retinoblastoma protein (pRb, RB)