title: MicroRNAs MiR-17, MiR-20a, and MiR-106b act in concert to modulate E2F activity on cell cycle arrest during neuronal lineage differentiation of USSC.
abstract: BACKGROUND
  MicroRNAs are short (∼22 nt) non-coding regulatory RNAs that control gene expression at the post-transcriptional level. Here the functional impact of microRNAs on cell cycle arrest during neuronal lineage differentiation of unrestricted somatic stem cells from human cord blood (USSC) was analyzed.
  
  
  RESULTS
  Expression profiling revealed downregulation of microRNAs miR-17, -20a, and -106b in USSC differentiated into neuronal lineage but not in USSC differentiated into osteogenic lineage. Transfection experiments followed by Ki67 immunostainings demonstrated that each of these microRNAs was able to promote proliferation of native USSC and to prevent in part cell cycle arrest during neuronal lineage differentiation of USSC. Bioinformatic target gene predictions followed by experimental target gene validations revealed that miR-17, -20a, and -106b act in a common manner by downregulating an overlapping set of target genes mostly involved in regulation and execution of G(1)/S transition. Pro-proliferative target genes cyclinD1 (CCND1) and E2F1 as well as anti-proliferative targets CDKN1A (p21), PTEN, RB1, RBL1 (p107), RBL2 (p130) were shown as common targets for miR-17, -20a, and -106b. Furthermore, these microRNAs also downregulate WEE1 which is involved in G(2)/M transition. Most strikingly, miR-17, -20a, and -106b were found to promote cell proliferation by increasing the intracellular activity of E2F transcription factors, despite the fact that miR-17, -20a, and -106b directly target the transcripts that encode for this protein family.
  
  
  CONCLUSIONS
  Mir-17, -20a, and -106b downregulate a common set of pro- and anti-proliferative target genes to impact cell cycle progression of USSC and increase intracellular activity of E2F transcription factors to govern G(1)/S transition.
authors.affiliation: University Düsseldorf, Medical Faculty, Institute for Transplantation Diagnostics and Cell Therapeutics, Düsseldorf, Germany.
authors.forename: Hans-Ingo
authors.initials: HI
authors.lastname: Trompeter
authors.forename: Hassane
authors.initials: H
authors.lastname: Abbad
authors.forename: Katharina M
authors.initials: KM
authors.lastname: Iwaniuk
authors.forename: Markus
authors.initials: M
authors.lastname: Hafner
authors.forename: Neil
authors.initials: N
authors.lastname: Renwick
authors.forename: Thomas
authors.initials: T
authors.lastname: Tuschl
authors.forename: Jessica
authors.initials: J
authors.lastname: Schira
authors.forename: Hans Werner
authors.initials: HW
authors.lastname: Müller
authors.forename: Peter
authors.initials: P
authors.lastname: Wernet
mesh_terms: D002453:Cell Cycle; D002454:Cell Differentiation; D019070:Cell Lineage / Q000235:genetics; D049109:Cell Proliferation; D015536:Down-Regulation; D050684:E2F Transcription Factors / Q000378:metabolism*; D005312:Fetal Blood / Q000166:cytology*; D016193:G1 Phase / Q000235:genetics; D006801:Humans; D035683:MicroRNAs / Q000502:physiology*; D009474:Neurons / Q000166:cytology*; D013234:Stem Cells / Q000166:cytology
chemical_list: D050684:E2F Transcription Factors; C542541:MIRN106 microRNA, human; C524941:MIRN17 microRNA, human; C534451:MIRN20a microRNA, human; D035683:MicroRNAs