title: The ZEB1 transcription factor acts in a negative feedback loop with miR200 downstream of Ras and Rb1 to regulate Bmi1 expression.
abstract: Ras mutations are frequent in cancer cells where they drive proliferation and resistance to apoptosis. However in primary cells, mutant Ras instead can cause oncogene-induced senescence, a tumor suppressor function linked to repression of the polycomb factor Bmi1, which normally regulates cell cycle inhibitory cyclin-dependent kinase inhibitors (cdki). It is unclear how Ras causes repression of Bmi1 in primary cells to suppress tumor formation while inducing the gene in cancer cells to drive tumor progression. Ras also induces the EMT transcription factor ZEB1 to trigger tumor invasion and metastasis. Beyond its well-documented role in EMT, ZEB1 is important for maintaining repression of cdki. Indeed, heterozygous mutation of ZEB1 is sufficient for elevated cdki expression, leading to premature senescence of primary cells. A similar phenotype is evident with Bmi1 mutation. We show that activation of Rb1 in response to mutant Ras causes dominant repression of ZEB1 in primary cells, but loss of the Rb1 pathway is a hallmark of cancer cells and in the absence of such Rb1 repression Ras induces ZEB1 in cancer cells. ZEB1 represses miR-200 in the context of a mutual repression loop. Because miR-200 represses Bmi1, induction of ZEB1 leads to induction of Bmi1. Rb1 pathway status then dictates the opposing effects of mutant Ras on the ZEB1-miR-200 loop in primary versus cancer cells. This loop not only triggers EMT, surprisingly we show it acts downstream of Ras to regulate Bmi1 expression and thus the critical decision between oncogene-induced senescence and tumor initiation.
authors.affiliation: From the Molecular Targets Program, James Brown Cancer Center.
authors.forename: Yongqing
authors.initials: Y
authors.lastname: Liu
authors.forename: Ester
authors.initials: E
authors.lastname: Sánchez-Tilló
authors.forename: Xiaoqin
authors.initials: X
authors.lastname: Lu
authors.forename: Li
authors.initials: L
authors.lastname: Huang
authors.forename: Brian
authors.initials: B
authors.lastname: Clem
authors.forename: Sucheta
authors.initials: S
authors.lastname: Telang
authors.forename: Alfred B
authors.initials: AB
authors.lastname: Jenson
authors.forename: Miriam
authors.initials: M
authors.lastname: Cuatrecasas
authors.forename: Jason
authors.initials: J
authors.lastname: Chesney
authors.forename: Antonio
authors.initials: A
authors.lastname: Postigo
authors.forename: Douglas C
authors.initials: DC
authors.lastname: Dean
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016922:Cellular Senescence / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015689:Oncogene Protein p21(ras) / Q000096:biosynthesis* / Q000235:genetics; D063150:Polycomb Repressive Complex 1 / Q000096:biosynthesis* / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis* / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism*; D016160:Retinoblastoma Protein / Q000096:biosynthesis* / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000071799:Zinc Finger E-box-Binding Homeobox 1
chemical_list: C489421:Bmi1 protein, mouse; D018398:Homeodomain Proteins; D035683:MicroRNAs; C543719:Mirn200 microRNA, mouse; D011518:Proto-Oncogene Proteins; D012334:RNA, Neoplasm; D016160:Retinoblastoma Protein; D014157:Transcription Factors; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1; D063150:Polycomb Repressive Complex 1; D015689:Oncogene Protein p21(ras)
keywords: Cancer; Cancer Biology; Cell Signaling; Epithelial Mesenchymal Transition; Senescence