Insulin‐like Growth Factor‐1 Impacts p53 Target Gene Induction in UVB‐irradiated Keratinocytes and Human Skin,Photochemistry and Photobiology

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Insulin‐like Growth Factor‐1 Impacts p53 Target Gene Induction in UVB‐irradiated Keratinocytes and Human Skin
Photochemistry and Photobiology ( IF 2.6 ) Pub Date : 2020-06-01 , DOI: 10.1111/php.13279
Abdulrahman M M Alkawar ₁ , Amber J Castellanos ₁ , Mae Alexandra Carpenter ₁ , Rebekah J Hutcherson ₁ , Mariyyah A O Madkhali ₁ , Ron Michael Johnson ₂ , Michael Bottomley ₃ , Michael G Kemp ₁

Affiliation

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.

中文翻译：

胰岛素样生长因子-1 影响 UVB 照射的角质形成细胞和人类皮肤中 p53 靶基因的诱导

肿瘤抑制蛋白 p53 通过激活减轻 UVB 辐射对 DNA 的破坏作用的基因转录，限制了对紫外线-B (UVB) 光照射的诱变。由于大多数非黑色素瘤皮肤癌 (NMSC) 发生在老年人身上，因此了解老年人皮肤微环境中的突变过程非常重要。基于先前的研究表明，老年皮肤表达的生长因子胰岛素样生长因子-1 (IGF-1) 水平低于年轻成人皮肤，因此研究了 IGF-1 在调节 p53 靶基因中的作用。体外角质形成细胞和体外人皮肤外植体。在两个实验系统中，发现 p53 靶基因 p21 和 DNA 聚合酶 eta (pol η) 的产物因 UVB 暴露而增加，通过在体外去除角质形成细胞 IGF-1 或用 IGF-1 受体拮抗剂处理体外角质形成细胞和人皮肤外植体，观察到这种诱导被部分消除。由于 p21 和 pol η 的功能是限制 UVB 暴露后诱变 DNA 的复制，这些结果表明老年人群中的 NMSC 风险可能是由于年龄依赖性的 IGF-1 信号减弱，破坏了皮肤中 p53 的功能。

更新日期：2020-06-01

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