Section of Dermatology, Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
J Biochem Mol Toxicol. 2013 Feb;27(2):184-91. doi: 10.1002/jbt.21451. Epub 2012 Nov 5.
Although ultraviolet A (UVA; 315-400 nm) has different physical and biological targets than ultraviolet B (UVB; 280-315 nm), the contribution of UVA to skin cancer susceptibility and its molecular basis remain largely unknown. Here we show that chronic UVA radiation suppresses phosphatase and tensin homolog (PTEN) expression at the mRNA level. Subchronic and acute UVA radiation also downregulated PTEN in normal human epidermal keratinocytes, skin culture, and mouse skin. At the molecular level, chronic UVA radiation decreased the transcriptional activity of the PTEN promoter in a methylation-independent manner, whereas it had no effect on the protein stability or mRNA stability of PTEN. In contrast, we found that UVA-induced activation of the Ras/ERK/AKT and NF-кB pathways plays an important role in UV-induced PTEN downregulation. Inhibiting extracellular signal-regulated kinases (ERK) or protein pinase B (AKT) increases PTEN expression. Our findings may provide unique insights into PTEN downregulation as a critical component of UVA's molecular impact during keratinocyte transformation.
尽管紫外线 A（UVA；315-400nm）与紫外线 B（UVB；280-315nm）具有不同的物理和生物学靶标，但 UVA 对皮肤癌易感性的贡献及其分子基础在很大程度上仍不清楚。在这里，我们发现慢性 UVA 辐射会在 mRNA 水平上抑制磷酸酶和张力蛋白同系物（PTEN）的表达。亚慢性和急性 UVA 辐射也会下调正常人表皮角质形成细胞、皮肤培养物和小鼠皮肤中的 PTEN。在分子水平上，慢性 UVA 辐射以非甲基化方式降低了 PTEN 启动子的转录活性，而对 PTEN 的蛋白质稳定性或 mRNA 稳定性没有影响。相比之下，我们发现 UVA 诱导的 Ras/ERK/AKT 和 NF-кB 通路的激活在 UV 诱导的 PTEN 下调中起着重要作用。抑制细胞外信号调节激酶（ERK）或蛋白激酶 B（AKT）可增加 PTEN 的表达。我们的研究结果可能为 PTEN 下调作为 UVA 对角质形成细胞转化过程中分子影响的关键组成部分提供独特的见解。
