Calcineurin signaling in the keratinocyte UVB response

描述（由申请人提供）：钙调蛋白（PP2B）是已知唯一受钙/钙调蛋白控制的丝氨酸/苏氨酸磷酸酶，是细胞内钙信号传导的关键介质。钙调磷酸酶在上皮细胞中的生化和生物学功能尚未得到充分的研究。在最近的工作中，我们已经表明钙调磷酸酶在角化细胞生长/分化控制和头发周期中起关键作用。目前的研究旨在验证钙调磷酸酶在角化细胞对UVB暴露的反应中发挥类似重要作用的假设，影响这些细胞的内在调节以及它们调节皮肤中其他细胞类型的能力。我们的方法将基于角化细胞特异性钙调磷酸酶B1基因（CnB1）的基因缺失，这对钙调磷酸酶在这些细胞中的活性至关重要。通过功能和生化分析的结合，我们将进一步验证钙调磷酸酶与p53和Notch信号通路在角化细胞进入细胞周期退出、凋亡和/或分化的内在决定中协同作用的假设。最后，通过体内和体外实验的结合，我们将验证钙调磷酸酶在UVB暴露的长期后果中发挥重要作用，维持角质形成细胞干细胞群和/或致癌。钙调磷酸酶是已知唯一受钙/钙调蛋白控制的丝氨酸/苏氨酸磷酸酶，也是细胞内钙信号传导的关键介质。钙调磷酸酶在上皮细胞中的生化和生物学功能尚未得到充分的研究。在最近的工作中，我们已经证明钙调磷酸酶在表皮细胞的生长/分化控制和毛发周期中起关键作用。我们建议探索钙调磷酸酶在表皮细胞对紫外线（UV）暴露的急性反应中发挥类似重要作用的假设，影响其行为的内在调节以及它们调节皮肤中其他细胞类型的能力。我们将进一步验证钙调磷酸酶在表皮细胞对紫外线暴露的长期反应中起重要作用的假设，特别是在维持干细胞群和/或致癌作用方面。

DESCRIPTION (provided by applicant): Calcineurin (PP2B) is the only known serine/threonine phosphatase under calcium/calmodulin control and a key mediator of intracellular calcium signaling. The biochemical and biological functions of Calcineurin in epithelial cells have been mostly unexplored. In recent work, we have shown that Calcineurin plays a key role in keratinocyte growth/differentiation control and the hair cycle. The present studies are designed to test the hypothesis that Calcineurin plays a similarly important role in the response of keratinocytes to UVB exposure, impinging on intrinsic regulation of these cells as well as their capability to modulate other cell types in the skin. Our approach will be based on a keratinocyte-specific genetic deletion of the Calcineurin B1 gene (CnB1), which is essential for Calcineurin activity in these cells. By a combination of functional and biochemical assays, we will test the further hypothesis that Calcineurin functions in concert with the p53 and Notch signaling pathways in the intrinsic decision of keratinocytes to enter cell cycle withdrawal, apoptosis and/or differentiation. Finally, by a combination of in vivo and in vitro assays, we will test the hypothesis that Calcineurin plays an important role for the long-term consequences of UVB exposure in maintenance of keratinocyte stem cell populations and/or carcinogenesis. Narrative Calcineurin is the only known serine/threonine phosphatase under calcium/calmodulin control and a key mediator of intracellular calcium signaling. The biochemical and biological functions of Calcineurin in epithelial cells have been mostly unexplored. In recent work, we have shown that Calcineurin plays a key role in growth/differentiation control of epidermal cells and the hair cycle. We propose to explore the hypothesis that Calcineurin plays a similarly important role in the acute response of epidermal cells to Ultraviolet Light (UV) exposure, impinging on intrinsic regulation of their behavior as well as their capability to modulate other cell types in the skin. We will further test the hypothesis that Calcineurin plays an essential function in the long term response of epidermal cells to UV exposure, specifically in maintenance of stem cell populations and/or carcinogenesis.