MicroRNA-191 triggers keratinocytes senescence by SATB1 and CDK6 downregulation.
Keratinocyte replicative senescence has an important role in time-dependent changes of the epidermis, a tissue with high turnover. Senescence encompasses growth arrest during which cells remain metabolically active but acquire a typical enlarged, vacuolar and flattened morphology. It is also accompanied by the expression of endogenous senescence-associated-β-galactosidase and specific gene expression profiles. MicroRNAs levels have been shown to be modulated during keratinocytes senescence, playing key roles in inhibiting proliferation and in the acquisition of senescent markers. Here, we identify miR-191 as an anti-proliferative and replicative senescence-associated miRNA in primary human keratinocytes. Its overexpression is sufficient per se to induce senescence, as evaluated by induction of several senescence-associated markers. We show that SATB1 and CDK6 3'UTRs are two miR-191 direct targets involved in this pathway. Cdk6 and Satb1 protein levels decrease during keratinocytes replicative senescence and their silencing by siRNA is able to induce a G1 block in cell cycle, accompanied by an increase in senescence-associated markers.
University of Tor Vergata, Department of Experimental Medicine and Biochemical Sciences, Via Montpellier 1, Rome 00133, Italy.
A M
AM
Lena
M
M
Mancini
P
P
Rivetti di Val Cervo
G
G
Saintigny
C
C
Mahé
G
G
Melino
E
E
Candi
D020413:3' Untranslated Regions / Q000235:genetics; D001483:Base Sequence; D002453:Cell Cycle / Q000235:genetics; D002460:Cell Line; D016922:Cellular Senescence / Q000235:genetics*; D051361:Cyclin-Dependent Kinase 6 / Q000235:genetics*; D015536:Down-Regulation; D020868:Gene Silencing; D006801:Humans; D015603:Keratinocytes / Q000502:physiology*; D036961:Matrix Attachment Region Binding Proteins / Q000235:genetics*; D035683:MicroRNAs / Q000235:genetics / Q000502:physiology*; D008969:Molecular Sequence Data
D020413:3' Untranslated Regions; C546177:MIRN191 microRNA, human; D036961:Matrix Attachment Region Binding Proteins; D035683:MicroRNAs; C076189:SATB1 protein, human; C495911:CDK6 protein, human; D051361:Cyclin-Dependent Kinase 6