title: Polycomb group protein PHF1 regulates p53-dependent cell growth arrest and apoptosis.
abstract: Polycomb group protein PHF1 is well known as a component of a novel EED-EZH2·Polycomb repressive complex 2 complex and plays important roles in H3K27 methylation and Hox gene silencing. PHF1 is also involved in the response to DNA double-strand breaks in human cells, promotes nonhomologous end-joining processes through interaction with Ku70/Ku80. Here, we identified another function of PHF1 as a potential p53 pathway activator in a pathway screen using luminescence reporter assay. Subsequent studies showed PHF1 directly interacts with p53 proteins both in vivo and in vitro and co-localized in nucleus. PHF1 binds to the C-terminal regulatory domain of p53. Overexpression of PHF1 elevated p53 protein level and prolonged its turnover. Knockdown of PHF1 reduced p53 protein level and its target gene expression both in normal state and DNA damage response. Mechanically, PHF1 protects p53 proteins from MDM2-mediated ubiquitination and degradation. Furthermore, we showed that PHF1 regulates cell growth arrest and etoposide-induced apoptosis in a p53-dependent manner. Finally, PHF1 expression was significantly down-regulated in human breast cancer samples. Taken together, we establish PHF1 as a novel positive regulator of the p53 pathway. These data shed light on the potential roles of PHF1 in tumorigenesis and/or tumor progression.
authors.affiliation: State Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Sciences, Fudan University, 220 Handan Road, Shanghai 200433, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.forename: Chenji
authors.initials: C
authors.lastname: Wang
authors.forename: Pingzhao
authors.initials: P
authors.lastname: Zhang
authors.forename: Kun
authors.initials: K
authors.lastname: Gao
authors.forename: Dejie
authors.initials: D
authors.lastname: Wang
authors.forename: Hongxiu
authors.initials: H
authors.lastname: Yu
authors.forename: Ting
authors.initials: T
authors.lastname: Zhang
authors.forename: Sirui
authors.initials: S
authors.lastname: Jiang
authors.forename: Saiyin
authors.initials: S
authors.lastname: Hexige
authors.forename: Zehui
authors.initials: Z
authors.lastname: Hong
authors.forename: Akira
authors.initials: A
authors.lastname: Yasui
authors.forename: Jun O
authors.initials: JO
authors.lastname: Liu
authors.forename: Haojie
authors.initials: H
authors.lastname: Huang
authors.forename: Long
authors.initials: L
authors.lastname: Yu
mesh_terms: D017209:Apoptosis; D001943:Breast Neoplasms / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D063146:Polycomb-Group Proteins / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D034622:RNA Interference; D014157:Transcription Factors / Q000737:chemistry / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D025801:Ubiquitin / Q000737:chemistry
chemical_list: D004268:DNA-Binding Proteins; C112309:PHF1 protein, human; D063146:Polycomb-Group Proteins; C495901:TP53 protein, human; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D025801:Ubiquitin; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2