title: miR-294/miR-302 promotes proliferation, suppresses G1-S restriction point, and inhibits ESC differentiation through separable mechanisms.
abstract: The miR-294 and miR-302 microRNAs promote the abbreviated G1 phase of the embryonic stem cell (ESC) cell cycle and suppress differentiation induced by let-7. Here, we evaluated the role of the retinoblastoma (Rb) family proteins in these settings. Under normal growth conditions, miR-294 promoted the rapid G1-S transition independent of the Rb family. In contrast, miR-294 suppressed the further accumulation of cells in G1 in response to nutrient deprivation and cell-cell contact in an Rb-dependent fashion. We uncovered five additional miRNAs (miR-26a, miR-99b, miR-193, miR-199a-5p, and miR-218) that silenced ESC self-renewal in the absence of other miRNAs, all of which were antagonized by miR-294 and miR-302. Four of the six differentiation-inducing miRNAs induced an Rb-dependent G1 accumulation. However, all six still silenced self-renewal in the absence of the Rb proteins. These results show that the miR-294/miR-302 family acts through Rb-dependent and -independent pathways to regulate the G1 restriction point and the silencing of self-renewal, respectively.
authors.affiliation: Peking-Tsinghua Joint Center for Life Sciences, Institute of Molecular Medicine, Peking University, Beijing 100871, China. yangming.wang@pku.edu.cn
authors.forename: Yangming
authors.initials: Y
authors.lastname: Wang
authors.forename: Collin
authors.initials: C
authors.lastname: Melton
authors.forename: Ya-Pu
authors.initials: YP
authors.lastname: Li
authors.forename: Archana
authors.initials: A
authors.lastname: Shenoy
authors.forename: Xin-Xin
authors.initials: XX
authors.lastname: Zhang
authors.forename: Deepa
authors.initials: D
authors.lastname: Subramanyam
authors.forename: Robert
authors.initials: R
authors.lastname: Blelloch
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D059585:G1 Phase Cell Cycle Checkpoints; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism*; D016160:Retinoblastoma Protein / Q000378:metabolism
chemical_list: C556303:MIRN294 microRNA, mouse; C558265:MIRN302 microRNA, mouse; D035683:MicroRNAs; D016160:Retinoblastoma Protein