Notch Cooperates with Survivin to Maintain Stemness and to Stimulate Proliferation in Human Keratinocytes during Ageing

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 de...

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Bibliographic Details
Published in:International journal of molecular sciences 2015-11, Vol.16 (11), p.26291-26302
Main Authors: Palazzo, Elisabetta, Morandi, Paolo, Lotti, Roberta, Saltari, Annalisa, Truzzi, Francesca, Schnebert, Sylvianne, Dumas, Marc, Marconi, Alessandra, Pincelli, Carlo
Format: Article
Language:English
Subjects:
Adolescent
Adult
Age Factors
Aged
Aging
Calcium - metabolism
Cell Proliferation
Cell Self Renewal
Cells
Cellular Senescence - genetics
Child
Child, Preschool
Gene expression
Humans
Infant
Infant, Newborn
Inhibitor of Apoptosis Proteins - metabolism
Keratinocytes - metabolism
Middle Aged
Protein Binding
Receptor, Notch1 - metabolism
Receptors, Notch - metabolism
Signal Transduction
Stem Cells - metabolism
Young Adult
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Summary: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.
ISSN:1422-0067
1661-6596
1422-0067
DOI:10.3390/ijms161125948