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首页> 外文期刊>Molecular and Cellular Biology >The UV (Ribotoxic) Stress Response of Human Keratinocytes Involves the Unexpected Uncoupling of the Ras-Extracellular Signal-Regulated Kinase Signaling Cascade from the Activated Epidermal Growth Factor Receptor
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The UV (Ribotoxic) Stress Response of Human Keratinocytes Involves the Unexpected Uncoupling of the Ras-Extracellular Signal-Regulated Kinase Signaling Cascade from the Activated Epidermal Growth Factor Receptor

机译：人类角质形成细胞的紫外线（核毒性）应激反应涉及从激活的表皮生长因子受体的Ras细胞外信号调节激酶信号级联的意外解偶联。

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In mammals, UVB radiation is of biological relevance primarily for the cells of the epidermis. We report here the existence of a UVB response that is specific for proliferating human epidermal keratinocytes. Unlike other cell types that also display a UVB response, keratinocytes respond to UVB irradiation with a transient but potent downregulation of the Ras-extracellular signal-regulated kinase (ERK) signaling cascade. The downregulation of ERK precedes a profound decrease in the steady-state levels of cyclin D1, a mediator of the proliferative action of ERK. Keratinocytes exhibit high constitutive activity of the Ras-ERK signaling cascade even in culture medium lacking supplemental growth factors. The increased activity of Ras and phosphorylation of ERK in these cells are maintained by the autocrine production of secreted molecules that activate the epidermal growth factor receptor (EGFR). Irradiation of keratinocytes increases the phosphorylation of EGFR on tyrosine residues Y845, Y992, Y1045, Y1068, Y1086, Y1148, and Y1173 above the basal levels and leads to the increased recruitment of the adaptor proteins Grb2 and ShcA and of a p55 form of the regulatory subunit of the phosphatidylinositide 3-kinase to the UVB-activated EGFR. Paradoxically, however, UVB causes, at the same time, the inactivation of Ras and a subsequent dephosphorylation of ERK. By contrast, the signaling pathway leading from the activated EGFR to the phosphorylation of PKB/Akt1 is potentiated by UVB. The UVB response of keratinocytes appeared to be a manifestation of the more general ribotoxic stress response inasmuch as the transduction of the UVB-generated inhibitory signal to Ras and ERK required the presence of active ribosomes at the time of irradiation.
机译：在哺乳动物中，UVB辐射主要对表皮细胞具有生物学意义。我们在这里报告了UVB反应的存在，该反应专门针对人类表皮角质形成细胞的增殖。与其他也显示UVB响应的细胞类型不同，角质形成细胞对UVB辐射的响应是短暂但有效的Ras细胞外信号调节激酶（ERK）信号级联反应的下调。 ERK的下调先于细胞周期蛋白D1（ERK增殖作用的调节剂）的稳态水平大幅下降。即使在缺乏补充生长因子的培养基中，角质形成细胞也表现出Ras-ERK信号级联的高组成型活性。这些细胞中Ras活性增加和ERK磷酸化通过分泌分泌的分子来自分泌产生，这些分子激活了表皮生长因子受体（EGFR）。照射角质形成细胞会增加酪氨酸残基Y845，Y992，Y1045，Y1068，Y1086，Y1148和Y1173上EGFR的磷酸化水平，使其高于基础水平，并导致衔接蛋白Grb2和ShcA以及p55形式的调节蛋白的募集增加。磷脂酰肌醇3激酶的亚基与UVB激活的EGFR。然而，自相矛盾的是，UVB同时导致Ras失活和随后ERK的去磷酸化。相比之下，UVB增强了从激活的EGFR到PKB / Akt1磷酸化的信号传导途径。角质形成细胞的UVB反应似乎是更普遍的核糖毒性应激反应的一种表现，因为UVB产生的抑制信号向Ras和ERK的转导需要在照射时存在活性核糖体。

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