Coordinate changes in gene expression which mark the spinous to granular cell transition in epidermis are regulated by protein kinase C.
Coordinate changes in gene expression which mark the spinous to granular cell transition in epidermis are regulated by protein kinase C.
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DOI：
10.1083/jcb.120.1.217
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发表时间：
1993-01
期刊：
影响因子：
--
通讯作者：
Yuspa SH
中科院分区：
文献类型：
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作者：
Dlugosz AA;Yuspa SH
皮肤的保护功能取决于严格调控的多步分化程序的成功完成，在此期间，表皮分化中特定阶段的标志物的诱导与在前一阶段表达的标志物的抑制相结合。我们已经使用体外模型系统探索了蛋白激酶C（PKC）在该过程中的作用，其中通过将培养基中的Ca 2+浓度从0.05提高至0.12 mM来诱导原代小鼠表皮角质形成细胞的培养物终末分化。12-O-十四烷酰基佛波醇-13-乙酸酯（TPA）和1-油酰基-2-乙酰基甘油在蛋白质和mRNA水平阻断Ca（2+）介导的棘细胞标记物角蛋白K1和K10的诱导。TPA和1-油酰基-2-乙酰甘油也迅速抑制K1和K10 mRNA的表达时，加入分化角质形成细胞培养物已经表达这些标志物。TPA对K1 mRNA表达的抑制作用在PKC已被苔藓抑素灭活的细胞中被阻断。TPA介导的K1 mRNA丢失在暴露于环己酰亚胺或放线菌素D的细胞中也被阻断，表明PKC诱导的蛋白质因子参与了这一过程。TPA处理的培养物中K1 mRNA的丢失是K1转录物的选择性不稳定和K1基因转录的快速抑制的结果。与棘细胞分化典型的mRNA的显著抑制相反，PKC的激活同时增强了颗粒细胞标志物兜甲蛋白和聚丝蛋白的mRNA和蛋白质的表达。在用苔藓抑素预处理的细胞中不发生这种反应。我们的研究结果表明，蛋白激酶C是一个基本的调节器的角质形成细胞的基因表达的协调变化，发生在表皮棘状颗粒细胞的过渡。
The protective function of skin depends on successful completion of a tightly regulated multi-step differentiation program, during which the induction of markers for a specific stage in epidermal differentiation is coupled to repression of markers expressed at the preceding stage. We have explored the role of protein kinase C (PKC) in this process using an in vitro model system, in which cultures of primary mouse epidermal keratinocytes are induced to terminally differentiate by raising the Ca2+ concentration in the medium from 0.05 to 0.12 mM. At doses which activate PKC, 12-O-tetradecanoylphorbol-13-acetate (TPA) and 1-oleoyl-2-acetylglycerol block Ca(2+)-mediated induction of the spinous cell markers keratins K1 and K10 at both the protein and mRNA level. TPA and 1-oleoyl-2-acetylglycerol also rapidly repress K1 and K10 mRNA expression when added to differentiating keratinocyte cultures already expressing these markers. The inhibition of K1 mRNA expression by TPA is blocked in cells where PKC has been inactivated with bryostatin. TPA-mediated loss of K1 mRNA is also blocked in cells exposed to cycloheximide or actinomycin D implicating a PKC-induced protein factor in this process. The loss of K1 mRNA in TPA-treated cultures is the result of both a selective destabilization of K1 transcripts and a rapid inhibition of K1 gene transcription. In contrast to the dramatic repression of mRNAs typical for spinous cell differentiation, activation of PKC concurrently enhances expression of mRNAs and proteins for the granular cell markers loricrin and filaggrin. This response does not occur in cells pre-treated with bryostatin to inactivate PKC. Our results suggest that PKC is a fundamental regulator of the coordinate changes in keratinocyte gene expression that occur during the spinous to granular cell transition in epidermis.