14-3-3σ regulates keratinocyte proliferation and differentiation by modulating Yap1 cellular localization.
14-3-3σ regulates keratinocyte proliferation and differentiation by modulating Yap1 cellular localization.
复制标题
14-3-3σ通过调节YAP1细胞定位来调节角质形成细胞的增殖和分化。
DOI：
10.1038/jid.2015.42
复制
发表时间：
2015-06
影响因子：
6.5
通讯作者：
Li, Qiutang
中科院分区：
文献类型：
--
作者：
Sambandam, Sumitha A. T.;Kasetti, Ramesh B.;Xue, Lei;Dean, Douglas C.;Lu, Qingxian;Li, Qiutang
编码14-3-3σ的基因的纯合重复脱毛（Er/Er）小鼠突变体显示以过度增殖的角质形成细胞和未分化的表皮为特征的表皮表型。杂合子Er/+小鼠发生自发性皮肤肿瘤，并且对促肿瘤的DMBA/TPA诱导高度敏感。14-3-3σ调控表皮增殖、分化和肿瘤形成的分子机制尚未得到很好的阐明。在本研究中，我们发现，Er/Er角质形成细胞未能隔离Yap 1在细胞质中，导致其核定位在表皮发育过程中在体内和分化诱导培养条件下在体外。此外，增强的Yap 1核定位在DMBA/TPA诱导的Er/+皮肤肿瘤中也是明显的。此外，在Er/Er角质形成细胞中，Yap 1表达的shRNA敲低抑制了它们的增殖，这表明YAP 1作为14-3-3σ的下游效应器控制表皮增殖。然后，我们证明角质形成细胞表达所有七种14-3-3蛋白同种型，其中一些与14-3-3σ形成异二聚体，全长WT或Er/Er小鼠中发现的突变形式。然而，Er 14-3-3σ不与Yap 1相互作用，如通过免疫共沉淀所证明的。我们的结论是，Er 14-3-3σ破坏了14-3-3和Yap 1之间的相互作用，因此未能阻断Yap 1的核转录功能，导致Er/Er表皮中祖细胞的持续扩增和分化抑制。
The homozygous repeated epilation (Er/Er) mouse mutant of the gene encoding 14-3-3σ 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 DMBA/TPA induction. The molecular mechanisms underlying 14-3-3σ regulation of epidermal proliferation, differentiation, and tumor formation have not been well elucidated. In the present 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 DMBA/TPA-induced tumors from Er/+ skin. Furthermore, shRNA knockdown of Yap1 expression in Er/Er keratinocytes inhibited their proliferation, suggesting that YAP1 functions as a downstream effector of 14-3-3σ controlling epidermal proliferation. We then demonstrated that keratinocytes express all seven 14-3-3 protein isoforms, some of which form heterodimers with 14-3-3σ, either full-length WT or the mutant form found in Er/Er mice. However Er 14-3-3σ does not interact with Yap1, as demonstrated by co-immunoprecipitation. We conclude that Er 14-3-3σ disrupts the interaction between 14-3-3 and Yap1, thus fails to block Yap1 nuclear transcriptional function, causing continued progenitor expansion and inhibition of differentiation in Er/Er epidermis.
登录
查看更多内容
DOI：
10.1126/science.1199010
发表时间：
2011-04-22
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Heallen T;Zhang M;Wang J;Bonilla-Claudio M;Klysik E;Johnson RL;Martin JF
通讯作者：
Martin JF
影响因子：
50.3
作者：
Zhou D;Conrad C;Xia F;Park JS;Payer B;Yin Y;Lauwers GY;Thasler W;Lee JT;Avruch J;Bardeesy N
通讯作者：
Bardeesy N
DOI：
10.1016/j.bbrc.2010.01.084
发表时间：
2010-02-19
影响因子：
3.1
作者：
Xin, Ying;Lu, Qingxian;Li, Qiutang
通讯作者：
Li, Qiutang
影响因子：
14.8
作者：
Tiscornia, Gustavo;Singer, Oded;Verma, Inder M.
通讯作者：
Verma, Inder M.
影响因子：
11.4
作者：
Kanai, F;Marignani, PA;Yaffe, MB
通讯作者：
Yaffe, MB