title: The miR-17 family links p63 protein to MAPK signaling to promote the onset of human keratinocyte differentiation.
abstract: The p63 protein plays a key role in regulating human keratinocyte proliferation and differentiation. Although some p63-regulating microRNAs (miRNAs) have been identified in the control of epidermal homeostasis, little is known about miRNAs acting downstream of p63. In this paper, we characterized multiple p63-regulated miRNAs (miR-17, miR-20b, miR-30a, miR-106a, miR-143 and miR-455-3p) and elucidated their roles in the onset of keratinocyte differentiation. We identified RB, p21 and multiple MAPKs as targets of these p63-controlled miRNAs. Upon inhibition of most of these miRNAs, we observed defects in commitment to differentiation that could be reversed by siRNA-mediated silencing of their targets. Furthermore, knockdown of MAPK8 and MAPK9 efficiently restored expression of the early differentiation markers keratin 1 and keratin 10 in p63-silenced primary human keratinocytes. These results highlight new mechanistic roles of multiple miRNAs, particularly the miR-17 family (miR-17, miR-20b and miR-106a), as regulatory intermediates for coordinating p63 with MAPK signaling in the commitment of human mature keratinocytes to early differentiation.
authors.affiliation: CEA, Laboratoire de Biologie à Grande Echelle, Grenoble, France.
authors.forename: Ning
authors.initials: N
authors.lastname: Wu
authors.forename: Eric
authors.initials: E
authors.lastname: Sulpice
authors.forename: Patricia
authors.initials: P
authors.lastname: Obeid
authors.forename: Sami
authors.initials: S
authors.lastname: Benzina
authors.forename: Frédérique
authors.initials: F
authors.lastname: Kermarrec
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Combe
authors.forename: Xavier
authors.initials: X
authors.lastname: Gidrol
mesh_terms: D000943:Antigens, Differentiation / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation; D002460:Cell Line; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism / Q000502:physiology*; D020935:MAP Kinase Signaling System; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D048055:Mitogen-Activated Protein Kinase 8 / Q000235:genetics / Q000378:metabolism; D048056:Mitogen-Activated Protein Kinase 9 / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D059467:Transcriptome; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology
chemical_list: D000943:Antigens, Differentiation; C542359:MIRN143 microRNA, human; C524941:MIRN17 microRNA, human; D035683:MicroRNAs; C115051:TP63 protein, human; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D048056:Mitogen-Activated Protein Kinase 9; D048055:Mitogen-Activated Protein Kinase 8