Increased Susceptibility to Skin Carcinogenesis Associated with a Spontaneous Mouse Mutation in the Palmitoyl Transferase Zdhhc13 Gene.
Increased Susceptibility to Skin Carcinogenesis Associated with a Spontaneous Mouse Mutation in the Palmitoyl Transferase Zdhhc13 Gene.
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DOI：
10.1038/jid.2015.314
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发表时间：
2015-12
期刊：
影响因子：
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通讯作者：
Benavides F
中科院分区：
文献类型：
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作者：
Perez CJ;Mecklenburg L;Jaubert J;Martinez-Santamaria L;Iritani BM;Espejo A;Napoli E;Song G;Del Río M;DiGiovanni J;Giulivi C;Bedford MT;Dent SYR;Wood RD;Kusewitt DF;Guénet JL;Conti CJ;Benavides F
在这里，我们描述了一个自发突变Zdhhc 13（锌指，DHHC域包含13）基因（也称为Hip 14 l），24个基因编码棕榈酰基转移酶（PAT）酶的小鼠。该突变（Zdhhc 13 luc）被鉴定为无义碱基取代，其导致提前终止密码子，产生截短形式的ZDHHC 13蛋白，代表潜在的功能丧失等位基因。纯合子Zdhhc 13 luc/Zdhhc 13 luc小鼠出现全身性毛发减少，与毛发周期异常、表皮和皮脂腺增生、角化过度和表皮厚度增加相关。与野生型表皮相比，在未处理的皮肤中以及在短期12-O-十四烷酰基-佛波醇-13-乙酸酯（TPA）处理和急性UVB暴露后，在突变体中观察到角质形成细胞增殖增加和从基底层到更分化层的加速转运。有趣的是，这种表皮表型与NF-κB（RelA）的组成性激活以及中性粒细胞募集和弹性蛋白酶活性增加相关。此外，肿瘤多样性和化学皮肤致癌后乳头状瘤的恶性进展显着高于突变型小鼠比野生型同窝。据我们所知，这是第一份关于PAT在皮肤癌发生中的保护作用的报告。
Here we describe a spontaneous mutation in the Zdhhc13 (zinc finger, DHHC domain containing 13) gene (also called Hip14l), one of 24 genes encoding palmitoyl acyltransferase (PAT) enzymes in the mouse. This mutation (Zdhhc13luc) was identified as a nonsense base substitution, which results in a premature stop codon that generates a truncated form of the ZDHHC13 protein, representing a potential loss-of-function allele. Homozygous Zdhhc13luc/Zdhhc13luc mice developed generalized hypotrichosis, associated with abnormal hair cycle, epidermal and sebaceous gland hyperplasia, hyperkeratosis and increased epidermal thickness. Increased keratinocyte proliferation and accelerated transit from basal to more differentiated layers were observed in mutant compared to wild-type epidermis, in untreated skin and after short-term 12-O-tetradecanoyl-phorbol-13-acetate (TPA) treatment and acute UVB exposure. Interestingly, this epidermal phenotype was associated with constitutive activation of NF-κB (RelA) and increased neutrophil recruitment and elastase activity. Furthermore, tumor multiplicity and malignant progression of papillomas after chemical skin carcinogenesis were significantly higher in mutant mice than wild-type littermates. To our knowledge, this is the first report of a protective role for a PAT in skin carcinogenesis.