title: Notch Cooperates with Survivin to Maintain Stemness and to Stimulate Proliferation in Human Keratinocytes during Ageing.
abstract: The Notch signaling pathway orchestrates cell fate by either inducing cell differentiation or maintaining cells in an undifferentiated state. This study aims to evaluate Notch expression and function in normal human keratinocytes. Notch1 is expressed in all epidermal layers, though to a different degree of intensity, with a dramatic decrease during ageing. Notch1 intracellular domain (N1ICD) levels are decreased during transit from keratinocyte stem cells (KSC) to transit amplifying (TA) cells, mimicking survivin expression in samples from donors of all ages. Calcium markedly reduces N1ICD levels in keratinocytes. N1ICD overexpression induces the up-regulation of survivin and the down-regulation of keratin 10 and involucrin, while increasing the S phase of the cell cycle. On the other hand, Notch1 inhibition (DAPT) dose-dependently decreases survivin, stimulates differentiation, and reduces keratinocyte proliferation in samples from donors of all ages. Silencing Notch downgrades survivin and increases keratin 10. In addition, Notch1 inhibition decreases survivin levels and proliferation both in KSC and TA cells. Finally, while survivin overexpression decreases keratinocyte differentiation and increases N1ICD expression both in KSC and TA cells, silencing survivin results in N1ICD down-regulation and an increase in differentiation markers. These results suggest that the Notch1/survivin crosstalk contributes to the maintenance of stemness in human keratinocytes.
authors.affiliation: Laboratory of Cutaneous Biology, Department of Surgical, Medical, Dental and Morphological Sciences, University of Modena and Reggio Emilia, via del Pozzo 71, Modena 41121, Italy. elisabetta.palazzo@gmail.com.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Palazzo
authors.affiliation: Laboratory of Cutaneous Biology, Department of Surgical, Medical, Dental and Morphological Sciences, University of Modena and Reggio Emilia, via del Pozzo 71, Modena 41121, Italy. 60645@studenti.unimore.it.
authors.forename: Paolo
authors.initials: P
authors.lastname: Morandi
authors.affiliation: Laboratory of Cutaneous Biology, Department of Surgical, Medical, Dental and Morphological Sciences, University of Modena and Reggio Emilia, via del Pozzo 71, Modena 41121, Italy. roberta.lotti@unimore.it.
authors.forename: Roberta
authors.initials: R
authors.lastname: Lotti
authors.affiliation: Laboratory of Cutaneous Biology, Department of Surgical, Medical, Dental and Morphological Sciences, University of Modena and Reggio Emilia, via del Pozzo 71, Modena 41121, Italy. annalisa.saltari@unimore.it.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Saltari
authors.affiliation: Laboratory of Cutaneous Biology, Department of Surgical, Medical, Dental and Morphological Sciences, University of Modena and Reggio Emilia, via del Pozzo 71, Modena 41121, Italy. francesca.truzzi@unimore.it.
authors.forename: Francesca
authors.initials: F
authors.lastname: Truzzi
authors.affiliation: LVMH Recherche, 185 Avenue de Verdun, Saint Jean de Braye 45800, France. sschnebert@research.lvmh-pc.com.
authors.forename: Sylvianne
authors.initials: S
authors.lastname: Schnebert
authors.affiliation: LVMH Recherche, 185 Avenue de Verdun, Saint Jean de Braye 45800, France. mdumas@research.lvmh-pc.com.
authors.forename: Marc
authors.initials: M
authors.lastname: Dumas
authors.affiliation: Laboratory of Cutaneous Biology, Department of Surgical, Medical, Dental and Morphological Sciences, University of Modena and Reggio Emilia, via del Pozzo 71, Modena 41121, Italy. alessandra.marconi@unimore.it.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Marconi
authors.affiliation: Laboratory of Cutaneous Biology, Department of Surgical, Medical, Dental and Morphological Sciences, University of Modena and Reggio Emilia, via del Pozzo 71, Modena 41121, Italy. carlo.pincelli@unimore.it.
authors.forename: Carlo
authors.initials: C
authors.lastname: Pincelli
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D002118:Calcium / Q000378:metabolism; D049109:Cell Proliferation; D000066673:Cell Self Renewal; D016922:Cellular Senescence / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism*; D015603:Keratinocytes / Q000378:metabolism*; D008875:Middle Aged; D011485:Protein Binding; D051881:Receptor, Notch1 / Q000378:metabolism; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction; D013234:Stem Cells / Q000378:metabolism*; D000077022:Survivin; D055815:Young Adult
chemical_list: C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D051881:Receptor, Notch1; D051880:Receptors, Notch; D000077022:Survivin; D002118:Calcium
keywords: Notch1; keratinocytes; stem cells; survivin