Transcriptional regulation of ataxia-telangiectasia and Rad3-related protein by activated p21-activated kinase-1 protects keratinocytes in UV-B-induced premalignant skin lesions.
Transcriptional regulation of ataxia-telangiectasia and Rad3-related protein by activated p21-activated kinase-1 protects keratinocytes in UV-B-induced premalignant skin lesions.
复制标题
激活的 p21 激活激酶 1 对共济失调毛细血管扩张和 Rad3 相关蛋白的转录调节可保护 UV-B 诱导的癌前皮肤病变中的角质形成细胞。
作者：
Beesetti,S;Mavuluri,J;Surabhi,RP;Oberyszyn,TM;Tober,K;Pitani,RS;Joseph,LD;Venkatraman,G;Rayala,SK
阳光引起的皮肤病变，特别是光化性角化病，通常被认为是癌前皮肤病变，如果不治疗，可进展为鳞状细胞癌（SCC）和浸润性SCC。因此，了解紫外线-B（UV-B）暴露的细胞受到保护的分子机制以及促进某些癌前皮肤病变进展为恶性病变的信号通路将使我们能够预防或治愈皮肤癌。在目前的研究中，我们发现磷酸化p21激活激酶-1（Pak 1）和Pak 1的表达是高的日光诱导的癌前皮肤病变的免疫组织化学评估的临床样本。此外，我们观察到，与未暴露的皮肤组织相比，在UV-B暴露的无毛SKH小鼠模型皮肤样品中磷酸化Pak 1和Pak 1水平高。我们在细胞系和动物模型中的研究结果表明，Pak 1在UV-B辐射下被激活，并且这种激活的Pak 1从细胞质易位到细胞核。在细胞核内，Pak 1通过C-Fos与DNA修复激酶ATR（毛细血管扩张性共济失调和Rad 3相关蛋白）的特定启动子区域结合，并充当ATR的转录调节因子。我们的分析结果表明，Pak 1过表达，敲低和Pak 1敲除细胞系模型表明，Pak 1赋予保护角质形成细胞从UV-B诱导的凋亡和DNA损伤通过ATR。据我们所知，这是第一项评估信号分子Pak 1在阳光诱导的癌前皮肤病变中的功能和临床意义的研究，并表明Pak 1活化和表达增加可以作为非黑色素瘤皮肤癌进展的早期预警信号，如果被忽视的话。
Sun-induced skin lesions, in particular actinic keratosis, are generally considered as premalignant skin lesions that can progress into squamous cell carcinoma (SCC) and invasive SCC if left untreated. Therefore, understanding the molecular mechanisms by which the ultraviolet-B (UV-B)-exposed cells are being protected and the signaling pathways that promote the progression of certain premalignant skin lesions to malignant lesions will permit us to prevent or cure skin cancers. In the current study, we found that phospho-p21-activated kinase-1 (Pak1) and Pak1 expression was high in clinical samples of sunlight-induced premalignant skin lesions assessed by immunohistochemistry. Further, we observed that phospho-Pak1 and Pak1 levels are high in UV-B-exposed hairless SKH mouse model skin samples as compared with unexposed skin tissue. Our results from cell line and animal models showed that Pak1 is activated in response to UV-B radiation, and this activated Pak1 translocates from the cytoplasm to the nucleus. Inside the nucleus, Pak1 via C-Fos binds to a specific promoter region of DNA repair kinase ATR (ataxia–telangiectasia and Rad3-related protein) and acts as a transcriptional regulator of ATR. Results from our analysis showed that Pak1 overexpression, knockdown and Pak1 knockout cell line models showed that Pak1 confers protection to keratinocytes from UV-B-induced apoptosis and DNA damage via ATR. To our knowledge, this is the first study that evaluates the functional and clinical significance of a signaling molecule, Pak1, in sun-induced premalignant skin lesions and indicates that increased Pak1 activation and expression could serve as an early warning sign of progression toward non-melanoma skin cancer, if ignored.