Targeted antizyme expression in the skin of transgenic mice reduces tumor promoter induction of ornithine decarboxylase and decreases sensitivity to chemical carcinogenesis.
Targeted antizyme expression in the skin of transgenic mice reduces tumor promoter induction of ornithine decarboxylase and decreases sensitivity to chemical carcinogenesis.
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发表时间：
2001-08
期刊：
影响因子：
11.2
通讯作者：
D. Feith;Lisa M. Shantz;Anthony E. Pegg
中科院分区：
文献类型：
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作者：
D. Feith;Lisa M. Shantz;Anthony E. Pegg
为了直接评估增加的鸟氨酸脱羧酶（ODC）和多胺在小鼠皮肤癌变中的作用，我们使用牛角蛋白5（K5）和角蛋白6（K6）启动子元件来指导抗酶（AZ）在特定皮肤细胞群中的表达。AZ是多胺代谢的多功能调节剂，其抑制ODC活性，刺激ODC降解，并抑制多胺摄取。在0和24小时用12-O-十四酰基佛波醇-13-乙酸酯（TPA）处理的K5-AZ小鼠表现出表皮和真皮ODC活性的增加，但幅度降低。由于TPA诱导的AZ蛋白表达，类似处理的K6-AZ小鼠在第二次施用后未显示任何增加的ODC活性或蛋白。在未处理的K5-AZ小鼠和TPA处理的K5-AZ和K6-AZ小鼠中，表皮和真皮多胺含量，特别是亚精胺含量降低。还研究了两个K6-AZ转基因系[K6-AZ（52）和K6-AZ（18）]和一个K5-AZ系对7，12-二甲基苯并（a）蒽/TPA致癌作用的敏感性。与正常同窝出生的小鼠相比，K6-AZ（52）小鼠的肿瘤发作明显延迟，肿瘤多样性降低>80%。K6-AZ（18）和K5-AZ小鼠也比同窝对照小鼠发生较少的乳头状瘤（分别为35%和50%），这些品系组合产生双转基因动物，肿瘤多样性增加（70%）。这些小鼠首次证明AZ在动物癌症模型中抑制肿瘤生长，并提供了一个有价值的模型系统来评估ODC和多胺在皮肤肿瘤发生中的作用。
To directly evaluate the role of increased ornithine decarboxylase (ODC) and polyamines in mouse skin carcinogenesis, we used bovine keratin 5 (K5) and keratin 6 (K6) promoter elements to direct the expression of antizyme (AZ) to specific skin cell populations. AZ is a multifunctional regulator of polyamine metabolism that inhibits ODC activity, stimulates ODC degradation, and suppresses polyamine uptake. K5-AZ mice treated with 12-O-tetradecanoylphorbol-13-acetate (TPA) at 0 and 24 h exhibit increases in epidermal and dermal ODC activity that are reduced in magnitude. K6-AZ mice treated similarly do not show any increased ODC activity or protein after a second application due to TPA-induced expression of AZ protein. Epidermal and dermal polyamine content, particularly spermidine, is reduced in untreated K5-AZ mice and TPA-treated K5-AZ and K6-AZ mice. Susceptibility to 7,12-dimethylbenz(a)anthracene/TPA carcinogenesis was also investigated for two K6-AZ transgenic lines [K6-AZ(52) and K6-AZ(18)] and a single K5-AZ line. K6-AZ(52) mice had a substantial delay in tumor onset and a >80% reduction in tumor multiplicity compared with normal littermates. K6-AZ(18) and K5-AZ mice also developed fewer papillomas than littermate controls (35% and 50%, respectively), and the combination of these lines to produce double transgenic animals yielded an additive decrease (70%) in tumor multiplicity. These mice demonstrate for the first time that AZ suppresses tumor growth in an animal cancer model and provide a valuable model system to evaluate the role of ODC and polyamines in skin tumorigenesis.