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Encouragement Award

机译：鼓励奖励

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Identification of the specific genetic variants responsible for the increased susceptibility to familial orsporadic cancers is essential. Using a forward genetics approach to map loci in 7, 12-dimethylbenz(a)anthracene (DMBA)/ 12-O-tetradecanoylphorbol-13-acetate (TPA) skin cancer model, we previouslyidentified a genetic locus Skin tumour modifier of MSM (Stmm1-12). We focused on Stmm1 on chromosome 7and have generated sub-congenic lines to identify the gene responsible for the effect of the locus. Weidentified parathyroid hormone (Pth) as the primary candidate for Stmm1. PTH is well known to act withvitamin D to regulate calcium and phosphate homeostasis. We identified higher iPTH levels in sera fromcancer-resistant MSM/Ms mice compared with susceptible FVB/NJ mice. Therefore, we performed skincarcinogenesis experiments with MSM-BAC transgenic mice and Pth knockout heterozygous mice. As aresult, the higher amounts of iPTH in sera conferred stronger resistance to skin tumours. Furthermore,we found that the coding SNP (Val28Met) localizes in the Pro-PTH encoding region, which is linked toprocessing efficacy and increased PTH secretion. Finally, we report that PTH increases intracellularcalcium in keratinocytes and promotes their terminal differentiation. Our data suggest that Pth is one ofthe genes responsible for Stmm1, and serum iPTH could serve as a prevention marker of skin cancer and atarget for new therapies. On the other hand, Stmm3 on chromosome 4 was initially identified as a p53-dependent modifier locus. Cdkn2a, a known tumour suppressor, was found in the Stmm3 locus. The Cdkn2alocus encodes two separate proteins, p16Ink4a and p19Arf, which are generated from alternative open readingframes. We provided evidence that the function of Stmm3 is dependent on p53, and that p19ArfMSM confersstronger resistance to papillomas than p16Ink4aMSM in skin carcinogenesis experiments. In addition, wefounded that the genetic polymorphism in p19Arf between MSM/Ms (Val) and FVB/N (Leu), which stabilizethe protein and cause the protein to be localized in the nucleus. Moreover, we demonstrated that thep19ArfMSM allele more efficiently activates the p53 pathway than the p19ArfFVB allele. Therefore, we concludedthat p19Arf is one of the genes of responsible for Stmm3.
机译：鉴定负责对家族性蛋白癌癌的易感性增加的特定遗传变异是必不可少的。使用前瞻性遗传学方法在7,12-二甲基（A）蒽（DMBA）/ 12-O-四甲酰基卟啉-13-醋酸甲酰基（TPA）皮肤癌模型中映射到基因座，我们以前识别了MSM的遗传基因座皮肤肿瘤改性剂（STMM1 -12）。我们专注于染色体上的STMM1 7，并产生亚先天性线以鉴定负责基因座效果的基因。 Weiderified甲状旁腺激素（PTH）作为STMM1的主要候选者。众所周知，pth采用vitamin d来调节钙和磷酸盐稳态。与易感FVB / NJ小鼠相比，我们鉴定了血清癌的血清中的更高的IPTH水平。因此，我们对MSM-BAC转基因小鼠和PTH敲除杂合小鼠进行了SkicinaRINACEINUSE实验。作为过程，血清中较高量的IPTH赋予皮肤肿瘤的耐抗性较强。此外，我们发现编码SNP（Val28met）定位在Pro-Pth编码区域中，该区域是连接的Toprocessing功效和增加的PTH分泌。最后，我们认为PTH在角质形成细胞中增加胞内碱并促进其末端分化。我们的数据表明，PTH是负责STMM1的基因之一，血清IPTH可以作为新疗法的皮肤癌和Atarget的预防标记。另一方面，染色体4上的STMM3最初被识别为P53依赖性改性座位。在STMM3基因座中发现了一种已知的肿瘤抑制剂CDKN2A。 CDKN2ALOCUS编码两个单独的蛋白质，P16ink4a和p19ARF，其由替代开放式读取帧产生。我们提供了证据表明STMM3的功能依赖于P53，并且P19ARFMSM在皮肤致癌实验中比P16ink4Amsm扩展到乳头瘤的抗性。此外，我们在MSM / MS（VAL）和FVB / N（LEU）之间的P19ARF中的遗传多态性，其稳定蛋白质并使蛋白质在细胞核中局部化。此外，我们证明了P19ARFMSM等位基因比P19ARFFVB等位基因更有效地激活P53途径。因此，我们结束了P19ARF是对STMM3负责的基因之一。

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    《Experimental Animals》 |2020年第supplement期|共2页
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