p63-microRNA feedback in keratinocyte senescence

Pia Rivetti Di Val Cervo, Anna Maria Lena, Milena Nicoloso, Simona Rossi, Mara Mancini, Huiqing Zhou, Gaelle Saintigny, Elena Dellambra, Teresa Odorisio, Christian Mahé, George Adrian Calin, Eleonora Candi, Gerry Melino

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Abstract

We investigated the expression of microRNAs (miRNAs) associated with replicative senescence in human primary keratinocytes. A cohort of miRNAs up-regulated in senescence was identified by genome-wide miRNA profiling, and their change in expression was validated in proliferative versus senescent cells. Among these, miRNA (miR)-138, -181a, -181b, and -130b expression increased with serial passages. miR-138, -181a, and -181b, but not miR- 130b, overexpression in proliferating cells was sufficient per se to induce senescence, as evaluated by inhibition of BrdU incorporation and quantification of senescence-activated β-galactosidase staining. We identified Sirt1 as a direct target of miR-138, -181a, and -181b, whereas ΔNp63 expression was inhibited by miR-130b. We also found that ΔNp63α inhibits miR-138, -181a, -181b, and -130b expression by binding directly to p63-responsive elements located in close proximity to the genomic loci of these miRNAs in primary keratinocytes. These findings suggest that changes in miRNA expression, by modulating the levels of regulatory proteins such as p63 and Sirt1, strongly contribute to induction of senescence in primary human keratinocytes, thus linking these two proteins. Our data also indicate that suppression of miR-138, -181a, -181b, and -130b expression is part of a growth-promoting strategy of ΔNp63α in epidermal proliferating cells.

Original languageEnglish
Pages (from-to)1133-1138
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number4
DOIs
Publication statusPublished - Jan 24 2012

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    Di Val Cervo, P. R., Lena, A. M., Nicoloso, M., Rossi, S., Mancini, M., Zhou, H., Saintigny, G., Dellambra, E., Odorisio, T., Mahé, C., Calin, G. A., Candi, E., & Melino, G. (2012). p63-microRNA feedback in keratinocyte senescence. Proceedings of the National Academy of Sciences of the United States of America, 109(4), 1133-1138. https://doi.org/10.1073/pnas.1112257109