A Polymorphic Variant in p19Arf Confers Resistance to Chemically Induced Skin Tumors by Activating the p53 Pathway
A Polymorphic Variant in p19Arf Confers Resistance to Chemically Induced Skin Tumors by Activating the p53 Pathway
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p19Arf 的多态性变体通过激活 p53 途径赋予对化学诱导的皮肤肿瘤的抵抗力
DOI：
10.1016/j.jid.2018.12.027
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发表时间：
2019
影响因子：
6.5
通讯作者：
Wakabayashi Y.
中科院分区：
文献类型：
--
作者：
Saito M;Okumura K;Isogai E;Araki K;Tanikawa C;Matsuda K;Kamijo T;Kominami R;Wakabayashi Y.
鉴定导致家族性或散发性癌症易感性增加的特定遗传变异是重要的。使用正向遗传学方法在小鼠皮肤癌模型中绘制这些基因座，我们先前确定了一个强大的遗传基因座Stmm 3，赋予对4号染色体上化学诱导的皮肤乳头状瘤的抗性。在这里，我们报告的细胞周期蛋白依赖性激酶抑制剂基因Cdkn 2a/p19 Arfa作为一个主要的负责基因的Stmm 3位点。我们提供的证据表明，Stmm 3的功能依赖于p53，并且p19 ArfMSM在体内比p16 Ink 4aMSM赋予更强的对乳头状瘤的抗性。此外，我们发现耐药株MSM/Ms（瓦尔）和敏感株FVB/N（Leu）之间p19 Arf的遗传多态性改变了乳头状瘤发展、恶性转化和上皮-间质转化的易感性。此外，我们证明了p19 ArfMSM等位基因在体外和体内比p19 ArfFV Ballele更有效地激活p53通路。此外，我们在日本人群中发现了与人类癌症风险相关的小鼠Cdkn 2a多态性附近的CDKN 2A多态性。Cdkn 2a和CDKN 2A的遗传多态性可能会影响小鼠和人类的癌症风险。
Identification of the specific genetic variants responsible for the increased susceptibility to familial or sporadic cancers is important. Using a forward genetics approach to map such loci in a mouse skin cancer model, we previously identified a strong genetic locus,Stmm3, conferring resistance to chemically induced skin papillomas on chromosome 4. Here, we report the cyclin-dependent kinase inhibitor geneCdkn2a/p19Arfas a major responsible gene for theStmm3locus. We provide evidence that the function ofStmm3is dependent onp53and thatp19ArfMSMconfers stronger resistance to papillomas thanp16Ink4aMSMin vivo. In addition, we found that genetic polymorphism inp19Arfbetween a resistant strain, MSM/Ms (Val), and a susceptible strain, FVB/N (Leu), alters the susceptibility to papilloma development, malignant conversion, and the epithelial–mesenchymal transition. Moreover, we demonstrated that thep19ArfMSMallele more efficiently activates the p53 pathway than thep19ArfFVBallele in vitro and in vivo. Furthermore, we found polymorphisms inCDKN2Ain the vicinity of a polymorphism in mouseCdkn2aassociated with the risk of human cancers in the Japanese population. Genetic polymorphisms inCdkn2aandCDKN2Amay affect the cancer risk in both mice and humans.