title: Suppression of RAD21 Induces Senescence of MDA-MB-231 Human Breast Cancer Cells Through RB1 Pathway Activation Via c-Myc Downregulation.
abstract: Cellular senescence impedes cancer progression by limiting uncontrolled cell proliferation. To identify new genetic events controlling senescence, we performed a small interfering RNA screening human cancer cells and identified a number of targets potentially involved in senescence of MDA-MB-231 human breast cancer cells. Importantly, we showed that knockdown of RAD21 resulted in the appearance of several senescent markers, including enhanced senescence-associated β-galactosidase activity and heterochromatin focus formation, as well as elevated p21 protein levels and RB1 pathway activation. Further biochemical analyses revealed that RAD21 knockdown led to the downregulation of c-Myc and its targets, including CDK4, a negative regulator of RB1, and blockedRB1 phosphorylation (pRB1), and the RB1-mediated transcriptional repression of E2F. Moreover, c-Myc downregulation was partially mediated by proteasome-dependent degradation within promyelocytic leukemia (PML) nuclear bodies, which were found to be highly abundant during RAD21 knockdown-induced senescence. Exogenous c-Myc reconstitution rescued cells from RAD21 silencing-induced senescence. Altogether, data arising from this study implicate a novel function of RAD21 in cellular senescence in MDA-MB-231 cells that is mainly dependent onRB1 pathway activation via c-Myc downregulation.
authors.affiliation: The Institute of Genetics and Cytology, Northeast Normal University, Changchun, 130024, China.|The First Affiliated Hospital, Jilin University, Changchun, 130012, China.
authors.forename: Shan
authors.initials: S
authors.lastname: Zhu
authors.affiliation: The Key Laboratory of Molecular Epigenetics of the Ministry of Education, Northeast Normal University, Changchun, 130020, China.
authors.forename: Li
authors.initials: L
authors.lastname: Zhao
authors.affiliation: The Institute of Genetics and Cytology, Northeast Normal University, Changchun, 130024, China.
authors.forename: Yueyang
authors.initials: Y
authors.lastname: Li
authors.affiliation: The Institute of Genetics and Cytology, Northeast Normal University, Changchun, 130024, China.
authors.forename: Pingfu
authors.initials: P
authors.lastname: Hou
authors.affiliation: The Institute of Genetics and Cytology, Northeast Normal University, Changchun, 130024, China.
authors.forename: Ruosi
authors.initials: R
authors.lastname: Yao
authors.affiliation: The Institute of Genetics and Cytology, Northeast Normal University, Changchun, 130024, China.
authors.forename: Jiang
authors.initials: J
authors.lastname: Tan
authors.affiliation: The University of Auckland, Grafton, Auckland, 1023, New Zealand.
authors.forename: Dongxu
authors.initials: D
authors.lastname: Liu
authors.affiliation: School of Life Sciences, Changchun Normal University, Changchun, 130032, China.
authors.forename: Liping
authors.initials: L
authors.lastname: Han
authors.affiliation: The Institute of Genetics and Cytology, Northeast Normal University, Changchun, 130024, China.
authors.forename: Baiqu
authors.initials: B
authors.lastname: Huang
authors.affiliation: The First Affiliated Hospital, Jilin University, Changchun, 130012, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Lu
authors.affiliation: The Institute of Genetics and Cytology, Northeast Normal University, Changchun, 130024, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics*; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000187:drug effects; D004268:DNA-Binding Proteins; D015536:Down-Regulation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000494:pharmacology*; D056286:Retinoblastoma Binding Proteins / Q000378:metabolism*; D015398:Signal Transduction; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C489427:MYC protein, human; D009687:Nuclear Proteins; D010750:Phosphoproteins; D016271:Proto-Oncogene Proteins c-myc; C429022:RAD21 protein, human; C000606393:RB1 protein, human; D034741:RNA, Small Interfering; D056286:Retinoblastoma Binding Proteins; D044767:Ubiquitin-Protein Ligases
keywords: MDA-MB-231; RAD21; RB1; SENESCENCE; c-Myc