Abstract
The epidermis, the outer layer of the skin composed of keratinocytes, is a stratified epithelium that functions as a barrier to protect the organism from dehydration and external insults. The epidermis develops depending on the transcription factor p63, a member of the p53 family of transcription factors. p63 is strongly expressed in the innermost basal layer where epithelial cells with high clonogenic and proliferative capacity reside. Deletion of p63 in mice results in a dramatic loss of all keratinocytes and loss of stratified epithelia, probably due to a premature proliferative rundown of the stem and transient amplifying cells. Here we report that microRNA (miR)-203 is induced in vitro in primary keratinocytes in parallel with differentiation. We found that miR-203 specifically targets human and mouse p63 3′-UTRs and not SOCS-3, despite bioinformatics alignment between miR-203 and SOCS-3 3′-UTR. We also show that miR-203 overexpression in proliferating keratinocytes is not sufficient to induce full epidermal differentiation in vitro. In addition, we demonstrate that miR-203 is downregulated during the epithelial commitment of embryonic stem cells, and that overexpression of miR-203 in rapidly proliferating human primary keratinocytes significantly reduces their clonogenic capacity. The results suggest that miR-203, by regulating the ΔNp63 expression level, is a key molecule controlling the p63-dependent proliferative potential of epithelial precursor cells both during keratinocyte differentiation and in epithelial development. In addition, we have shown that miR-203 can regulate ΔNp63 levels upon genotoxic damage in head and neck squamous cell carcinoma cells, thus controlling cell survival.
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Abbreviations
- ES cells:
-
embryonic stem cells
- HEK:
-
human epidermal keratinocytes
- HNSCC:
-
head and neck squamous cell carcinomas
- K:
-
keratin
- miR:
-
microRNA
- p63−/−:
-
mouse knockout for p63
- TA:
-
transactivation domain
- TA cells:
-
transient amplifying cells
- TG:
-
transglutaminase
- ΔN:
-
amino-terminal truncated protein
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Acknowledgements
We thank Dr. Alessandro Giamboi Miraglia for technical support and Angelo Peschiaroli and Alessandro Terrinoni for scientific discussion. The work reported in this manuscript has been supported by the Medical Research Council (GM) and by grants from Telethon (GGP02251 to EC), AIRC (2743 to GM), EU (LSGBH-2005-019067-Epistem; LSHC-CT-2004-503576-Active p53) to GM, MIUR to GM, PRIN 06 to EC, PRIN 06 to GM, MinSan to GM, and by ANR (ANR-06-BLAN-0367) and EU (LSGBH-2005-019067-Epistem) to DA.
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Lena, A., Shalom-Feuerstein, R., di Val Cervo, P. et al. miR-203 represses ‘stemness’ by repressing ΔNp63. Cell Death Differ 15, 1187–1195 (2008). https://doi.org/10.1038/cdd.2008.69
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DOI: https://doi.org/10.1038/cdd.2008.69
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