| First Author | Sambandam SAT | Year | 2015 |
| Journal | J Invest Dermatol | Volume | 135 |
| Issue | 6 | Pages | 1621-1628 |
| PubMed ID | 25668240 | Mgi Jnum | J:221062 |
| Mgi Id | MGI:5637877 | Doi | 10.1038/jid.2015.42 |
| Citation | Sambandam SA, et al. (2015) 14-3-3sigma regulates keratinocyte proliferation and differentiation by modulating yap1 cellular localization. J Invest Dermatol 135(6):1621-8 |
| abstractText | The homozygous repeated epilation (Er/Er) mouse mutant of the gene encoding 14-3-3sigma displays an epidermal phenotype characterized by hyperproliferative keratinocytes and undifferentiated epidermis. Heterozygous Er/+ mice develop spontaneous skin tumors and are highly sensitive to tumor-promoting 7,12-dimethylbenzanthracene/12-O-tetradecanoyl-phorbol-13-acetate induction. The molecular mechanisms underlying 14-3-3sigma regulation of epidermal proliferation, differentiation, and tumor formation have not been well elucidated. In this study, we found that Er/Er keratinocytes failed to sequester Yap1 in the cytoplasm, leading to its nuclear localization during epidermal development in vivo and under differentiation-inducing culture conditions in vitro. In addition, enhanced Yap1 nuclear localization was also evident in 7,12-dimethylbenzanthracene/12-O-tetradecanoyl-phorbol-13-acetate-induced tumors from Er/+ skin. Furthermore, short hairpin RNA (shRNA) knockdown of Yap1 expression in Er/Er keratinocytes inhibited their proliferation, suggesting that YAP1 functions as a downstream effector of 14-3-3sigma controlling epidermal proliferation. We then demonstrated that keratinocytes express all seven 14-3-3 protein isoforms, some of which form heterodimers with 14-3-3sigma, either full-length wild type (WT) or the mutant form found in Er/Er mice. However, Er 14-3-3sigma does not interact with Yap1, as demonstrated by coimmunoprecipitation. We conclude that Er 14-3-3sigma disrupts the interaction between 14-3-3 and Yap1, and thus fails to block Yap1 nuclear transcriptional function, causing continued progenitor expansion and inhibition of differentiation in the Er/Er epidermis. |
