title: miR-34a is essential for p19(Arf)-driven cell cycle arrest.
abstract: The Arf tumor suppressor gene product, p19(Arf), regulates cell proliferation in incipient cancer cells and during embryo development. Beyond its commonly accepted p53-dependent actions, p19(Arf) also acts independently of p53 in both contexts. One such p53-independent effect with in vivo relevance includes its repression of Pdgfrβ, a process that is essential for vision in the mouse. We have utilized cell culture-based and mouse models to define a new role for miR-34a in this process. Ectopic expression of Arf in cultured cells enhanced the expression of several microRNAs predicted to target Pdgfrß synthesis, including the miR-34 family. Because miR-34a has been implicated as a p53-dependent effector, we investigated whether it also contributed to p53-independent effects of p19(Arf). Indeed, in mouse embryo fibroblasts (MEFs) lacking p53, Arf-driven repression of Pdgfrβ and its blockade of Pdgf-B stimulated DNA synthesis were both completely interrupted by anti-microRNA against miR-34a. Ectopic miR-34a directly targeted Pdgfrβ and a plasmid reporter containing wild-type Pdgfrβ 3'UTR sequence, but not one in which the miR-34a target sequence was mutated. Although miR-34a expression has been linked to p53-a well-known effector of p19(Arf)-Arf expression and its knockdown correlated with miR-34a level in MEFs lacking p53. Finally, analysis of the mouse embryonic eye demonstrated that Arf controlled expression of miR-34a, and the related miR-34b and c, in vivo during normal mouse development. Our findings indicate that miR-34a provides an essential link between p19(Arf) and its p53-independent capacity to block cell proliferation driven by Pdgfrβ. This has ramifications for developmental and tumor suppressor roles of Arf.
authors.affiliation: Division of Hematology/Oncology; Department of Pediatrics; University of Texas Southwestern Medical Center; Dallas, TX USA.
authors.forename: Nida
authors.initials: N
authors.lastname: Iqbal
authors.affiliation: Division of Hematology/Oncology; Department of Pediatrics; University of Texas Southwestern Medical Center; Dallas, TX USA; College of Fisheries; Key Laboratory of Freshwater Animal Breeding; Ministry of Agriculture; Huazhong Agricultural University; Wuhan, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Mei
authors.affiliation: Division of Hematology/Oncology; Department of Pediatrics; University of Texas Southwestern Medical Center; Dallas, TX USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Liu
authors.affiliation: Division of Hematology/Oncology; Department of Pediatrics; University of Texas Southwestern Medical Center; Dallas, TX USA; Center for Cancer and Blood Disorders; Children's Medical Center; Dallas, TX USA.
authors.forename: Stephen X
authors.initials: SX
authors.lastname: Skapek
mesh_terms: D000818:Animals; D059447:Cell Cycle Checkpoints / Q000235:genetics*; D002460:Cell Line; D049109:Cell Proliferation; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism*; D005123:Eye / Q000196:embryology / Q000378:metabolism; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000378:metabolism*; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; C551848:MIRN34a microRNA, mouse; D035683:MicroRNAs; D016159:Tumor Suppressor Protein p53; D020797:Receptor, Platelet-Derived Growth Factor beta
keywords: Pdgfrβ; cell cycle; miR-34a; p19Arf; p53; tumor suppression; vascular remodeling