Departments of Pharmacology and Toxicology, Boonshoft School of Medicine, Wright State University, Dayton, OH.
Department of Surgery, Boonshoft School of Medicine, Wright State University, Dayton, OH.
Photochem Photobiol. 2020 Nov;96(6):1332-1341. doi: 10.1111/php.13279. Epub 2020 Jun 1.
The tumor suppressor protein p53 limits mutagenesis in response to ultraviolet-B (UVB) light exposure by activating the transcription of genes that mitigate the damaging effects of UVB radiation on DNA. Because most nonmelanoma skin cancers (NMSCs) occur in older individuals, it is important to understand the process of mutagenesis in the geriatric skin microenvironment. Based on previous studies demonstrating that geriatric skin expresses lower levels of the growth factor insulin-like growth factor-1 (IGF-1) than young adult skin, a role for IGF-1 in the regulation of p53 target genes was investigated in both human keratinocytes in vitro and human skin explants ex vivo. The products of the p53 target genes p21 and DNA polymerase eta (pol η) were found to be increased by UVB exposure in both experimental systems, and this induction was observed to be partially abrogated by depriving keratinocytes of IGF-1 in vitro or by the treatment of keratinocytes in vitro and human skin explants with an IGF-1 receptor antagonist. Because p21 and pol η function to limit mutagenic DNA replication following UVB exposure, these results suggest that NMSC risk in geriatric populations may be due to age-dependent decreases in IGF-1 signaling that disrupt p53 function in the skin.
抑癌蛋白 p53 通过激活减轻 UVB 辐射对 DNA 损伤作用的基因转录，限制因暴露于紫外线-B（UVB）而发生的突变。由于大多数非黑色素瘤皮肤癌（NMSC）发生在老年人中，因此了解老年皮肤微环境中的突变过程非常重要。基于先前的研究表明，与年轻成年人皮肤相比，老年皮肤表达的生长因子胰岛素样生长因子-1（IGF-1）水平较低，因此研究人员在体外培养的人角质形成细胞和人体皮肤外植体中研究了 IGF-1 在调节 p53 靶基因中的作用。结果发现，在这两个实验系统中，p53 靶基因 p21 和 DNA 聚合酶 eta（pol η）的产物因 UVB 暴露而增加，并且这种诱导作用可通过体外剥夺角质形成细胞中的 IGF-1 或通过 IGF-1 受体拮抗剂处理体外培养的角质形成细胞和人体皮肤外植体而部分消除。因为 p21 和 pol η 的功能是限制 UVB 暴露后致突变的 DNA 复制，所以这些结果表明，老年人中 NMSC 的风险可能是由于 IGF-1 信号的年龄依赖性降低，从而破坏了 p53 在皮肤中的功能。
