Targeted expression of spermidine/spermine N1-acetyltransferase increases susceptibility to chemically induced skin carcinogenesis
Targeted expression of spermidine/spermine N1-acetyltransferase increases susceptibility to chemically induced skin carcinogenesis
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DOI：
10.1093/carcin/23.2.359
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发表时间：
2002-02-01
期刊：
影响因子：
4.7
通讯作者：
O'Brien, TG
中科院分区：
文献类型：
--
作者：
Coleman, CS;Pegg, AE;O'Brien, TG
利用牛角蛋白6基因启动子将亚精胺/精胺n -1乙酰转移酶（SSAT）靶向表达到转基因小鼠毛囊表皮角质形成细胞中。K6-SSAT转基因小鼠在表型上似乎是正常的，并且与正常的窝鼠无法区分，直到进行两阶段肿瘤发生方案。在这种肿瘤发生研究中，将小鼠饲养到抗肿瘤启动子的C57BL/6背景菌株上六代。K6-SSAT转基因小鼠在单次施用400 nmol肿瘤启动剂7,12-二甲基苯[a]蒽，然后每周两次施用17 nmol肿瘤启动剂12- o - tetradecanoylphorpol -13-acetate，连续19周后，表皮肿瘤数量增加了10倍。来自转基因动物的肿瘤样本显示，与非转基因动物的肿瘤相比，SSAT酶活性和SSAT蛋白水平显著升高，并且伴随的腐胺和n- 1-乙酰亚精胺池的变化表明转基因动物激活了SSAT介导的多胺分解代谢。在该模型中，肉眼和组织学都显示异常高数量的肿瘤进展为癌，这些肿瘤发生在早期潜伏期，并且仅在携带K6-SSAT转基因的小鼠中发生。这些结果表明，多胺分解代谢的激活导致腐胺和n -1-乙酰亚精胺的增加可能在化学诱导的小鼠皮肤肿瘤中起关键作用。
The bovine keratin 6 gene promoter was used to target expression of spermidine/spermine N-1-acetyltransferase (SSAT) to epidermal keratinocytes in the hair follicle of transgenic mice. K6-SSAT transgenic mice appeared to be phenotypically normal and were indistinguishable from normal littermates until subjected to a two-stage tumorigenesis protocol. For such tumorigenesis studies, mice were bred for six generations onto a tumor promoter resistant C57BL/6 background strain. K6-SSAT transgenic mice showed a 10-fold increase in the number of epidermal tumors that developed in response to a single application of 400 nmol of the tumor initiator 7,12-dimethylbenz[a]anthracene followed by twice weekly applications of 17 nmol of the tumor promoter 12-O-tetradecanoylphorbol-13-acetate for 19 weeks. Tumor samples from transgenic animals showed marked elevations in SSAT enzyme activity and SSAT protein levels compared with tumors from non-transgenic littermates, and the accompanying changes in putrescine and N-1-acetylspermidine pools indicated activation of SSAT-mediated polyamine catabolism in transgenic animals. An unusually high number of tumors were shown both grossly and histologically to have progressed to carcinomas in this model and these occurred with an early latency and only in mice carrying the K6-SSAT transgene. These results suggest that activation of polyamine catabolism leading to increases in putrescine and N-1-acetylspermidine may play a key role in chemically induced mouse skin neoplasia.