An active role of the DeltaN isoform of p63 in regulating basal keratin genes K5 and K14 and directing epidermal cell fate.
An active role of the DeltaN isoform of p63 in regulating basal keratin genes K5 and K14 and directing epidermal cell fate.
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DOI：
10.1371/journal.pone.0005623
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发表时间：
2009-05-20
期刊：
影响因子：
3.7
通讯作者：
Sinha S
中科院分区：
文献类型：
--
作者：
Romano RA;Ortt K;Birkaya B;Smalley K;Sinha S
复层上皮的基底角化细胞的一个主要定义特征是角蛋白基因K5和K14的表达。这两个基因的时空表达通常在转录水平上受到紧密协调的调控。这确保了K5和K14蛋白的专性配对，以产生对于增殖性角质形成细胞的结构和功能至关重要的中间丝（IF）网络。我们前期的研究表明，基底细胞限制性转录因子p63是K14基因的直接调节因子。在这里，我们提供的证据表明，p63，特别是ΔN亚型也调节K5基因的表达，通过结合到5′上游区域内的保守增强子。通过使用针对Δ Np 63的特异性抗体，我们发现在早期胚胎皮肤发育过程中，基础角蛋白和Δ Np 63蛋白的表达是一致的，但TAp 63亚型的表达不一致。我们证明，与以前的报告相反，在肺上皮中表达Δ Np 63的转基因小鼠表现出鳞状上皮化生，从头诱导K5和K14以及向表皮细胞谱系的转分化。有趣的是，Δ Np 63的体内表皮诱导特性不需要C-末端SAM结构域。最后，我们表明，Δ Np 63单独可以恢复基础角蛋白的表达，并重新启动p63缺失动物皮肤中失败的表皮分化程序。Δ Np 63是角质形成细胞分层程序的关键介质，并直接调节基础角蛋白基因。
One major defining characteristic of the basal keratinocytes of the stratified epithelium is the expression of the keratin genes K5 and K14. The temporal and spatial expression of these two genes is usually tightly and coordinately regulated at the transcriptional level. This ensures the obligate pairing of K5 and K14 proteins to generate an intermediate filament (IF) network that is essential for the structure and function of the proliferative keratinocytes. Our previous studies have shown that the basal-keratinocyte restricted transcription factor p63 is a direct regulator of K14 gene. Here we provide evidence that p63, specifically the ΔN isoform also regulates the expression of the K5 gene by binding to a conserved enhancer within the 5′ upstream region. By using specific antibodies against ΔNp63, we show a concordance in the expression between basal keratins and ΔNp63 proteins but not the TAp63 isoforms during early embryonic skin development. We demonstrate, that contrary to a previous report, transgenic mice expressing ΔNp63 in lung epithelium exhibit squamous metaplasia with de novo induction of K5 and K14 as well as transdifferentiation to the epidermal cell lineage. Interestingly, the in vivo epidermal inductive properties of ΔNp63 do not require the C-terminal SAM domain. Finally, we show that ΔNp63 alone can restore the expression of the basal keratins and reinitiate the failed epidermal differentiation program in the skin of p63 null animals. ΔNp63 is a critical mediator of keratinocyte stratification program and directly regulates the basal keratin genes.