Protein kinase D distribution in normal human epidermis, basal cell carcinoma and psoriasis
Protein kinase D distribution in normal human epidermis, basal cell carcinoma and psoriasis
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DOI：
10.1111/j.1365-2133.2005.07073.x
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发表时间：
2006-04-01
影响因子：
10.3
通讯作者：
Bollag, WB
中科院分区：
文献类型：
--
作者：
Ristich, VL;Bowman, PH;Bollag, WB
背景角质形成细胞在表皮的正常分层过程中经历确定的增殖和分化程序。控制这一过程的信号通路异常可能导致过度增殖性皮肤病的发病机制，包括牛皮癣和基底细胞癌（BCC）。我们之前提出蛋白激酶 D (PKD) 是角质形成细胞中的一种增殖信号酶，并推测其水平或调节异常可能导致皮肤过度增殖性疾病。 目的 为了确定过度增殖性人类皮肤疾病是否以 PKD 蛋白表达或分布异常为特征，将正常人表皮与基底细胞癌、未受累和受累银屑病表皮进行比较。对小鼠角质形成细胞进行样品和蛋白质印迹分析。使用磷酸特异性 PKD 抗体对肿瘤小鼠细胞进行蛋白质印迹分析，可以估计 PKD 激活状态。 结果 正常人表皮显示 PKD 蛋白在基底层（增殖性表皮区室）中表达为主，而整个基底层的相对表达量降低。未受累的银屑病皮肤表现出类似的模式，但相反，银屑病皮损表现出 PKD 染色在所有层中的弥漫分布。大多数检查的 BCC 显示出显着的 PKD 蛋白水平，并且在可以比较水平的活组织检查中，相对于正常表皮，PKD 水平升高。在肿瘤性小鼠角质形成细胞系中，PKD 水平和激活状态也有所增加。结论 PKD 在过度增殖性人类皮肤病、基底细胞癌和牛皮癣以及肿瘤性小鼠角质形成细胞中升高或分布错误。我们推测 PKD 在表皮中发挥增殖和/或抗分化作用，并且 PKD 的异常分布和/或激活可能参与促进或维持基底细胞癌和银屑病的疾病过程。
Background Keratinocytes undergo a defined programme of proliferation and differentiation during normal stratification of the epidermis. Anomalies in the signalling pathways controlling this process probably contribute to the pathogenesis of hyperproliferative dermatological diseases, including psoriasis and basal cell carcinoma (BCC). We have previously proposed that protein kinase D (PKD) is a proproliferative signalling enzyme in keratinocytes and have speculated that abnormalities in its levels or regulation may contribute to hyperproliferative disorders of the skin.Objectives To determine if hyperproliferative human skin disorders are characterized by abnormal protein expression or distribution of PKD, normal human epidermis was compared with BCC and uninvolved and involved psoriatic epidermis.Methods To examine protein expression, immunohistochemical analysis of human samples and Western blotting of neoplastic mouse keratinocytes was performed. Western analysis of neoplastic mouse cells using a phosphospecific PKD antibody allowed estimation of PKD activation status.Results Normal human epidermis demonstrated predominant PKD protein expression in the stratum basalis, the proliferative epidermal compartment, with decreased relative expression throughout the suprabasal strata. Uninvolved psoriatic skin showed a similar pattern, but in contrast, psoriatic lesions demonstrated a diffuse distribution of PKD staining throughout all strata. The majority of BCCs examined showed significant PKD protein levels and, in those biopsies in which the levels could be compared, elevated PKD levels relative to normal epidermis. PKD levels and activation status were also increased in a neoplastic mouse keratinocyte cell line.Conclusions PKD was elevated or misdistributed in the hyperproliferative human skin disorders, BCC and psoriasis, as well as neoplastic mouse keratinocytes. We speculate that PKD exerts proproliferative and/or antidifferentiative effects in the epidermis, and that anomalous distribution and/or activation of PKD may be involved in precipitating or sustaining the disease process in BCC and psoriasis.