Induction of ornithine decarboxylase activity is a necessary step for mitogen-activated protein kinase kinase-induced skin tumorigenesis.
Induction of ornithine decarboxylase activity is a necessary step for mitogen-activated protein kinase kinase-induced skin tumorigenesis.
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DOI：
10.1158/0008-5472.572.65.2
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发表时间：
2005-01
期刊：
影响因子：
11.2
通讯作者：
D. Feith;D. Bol;J. Carboni;M. Lynch;S. Sass-Kuhn;Paula L Shoop;L. Shantz
中科院分区：
文献类型：
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作者：
D. Feith;D. Bol;J. Carboni;M. Lynch;S. Sass-Kuhn;Paula L Shoop;L. Shantz
一种过表达MEK1 （Ras的下游效应物，由角蛋白14 （K14）启动子驱动）组成活性突变的转基因小鼠系已被用于验证以下假设：在肿瘤促进过程中，单一启动事件（即Raf/丝裂原活化蛋白激酶激酶/细胞外信号调节激酶（Raf/MEK/ERK）途径的激活）诱导鸟氨酸脱羧酶（ODC）是皮肤癌发生的必要步骤。K14-MEK小鼠表现为中度增生，在出生5周内出现自发性皮肤肿瘤。对表皮和真皮层的分析显示，MEK蛋白和ERK1/ERK2磷酸化被诱导，但Akt-1未发生变化，表明ras下游的另一条通路PI 3-激酶途径未被激活。肿瘤检查显示高水平的ODC蛋白和活性，表明依赖于MEK活性的信号级联的激活是ODC诱导的充分刺激。当K14-MEK小鼠从出生开始就在饮用水中给予α -二氟甲基鸟氨酸（一种ODC的自杀灭活剂）时，肿瘤生长的开始明显延迟（约6周），只有25%的DFMO处理的小鼠在15周龄时发生肿瘤。所有未经处理的K14-MEK小鼠在6周龄时均出现肿瘤。用DFMO治疗荷瘤小鼠，在几周内肿瘤大小和肿瘤数量均减少。肿瘤消退是肿瘤增殖抑制和细胞凋亡增加的结果。研究结果表明，ODC激活是Raf/MEK/ERK通路的重要组成部分，并确定K14-MEK小鼠是研究ODC在ras癌变中的调控的有价值的模型。
A transgenic mouse line overexpressing a constitutively active mutant of MEK1, a downstream effector of Ras, driven by the keratin 14 (K14) promoter, has been used to test the hypothesis that ornithine decarboxylase (ODC) induction during tumor promotion following a single initiating event [i.e., the activation of the Raf/mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (Raf/MEK/ERK) pathway], is a necessary step in skin carcinogenesis. K14-MEK mice exhibit moderate hyperplasia, with spontaneous skin tumor development within 5 weeks of birth. Analysis of epidermis and dermis showed induction of MEK protein and ERK1/ERK2 phosphorylation, but no change in Akt-1, suggesting that the PI 3-kinase pathway, another pathway downstream of ras, is not activated. Examination of tumors revealed high levels of ODC protein and activity, indicating that activation of signaling cascades dependent on MEK activity is a sufficient stimulus for ODC induction. When K14-MEK mice were given alpha-difluoromethylornithine (DFMO), a suicide inactivator of ODC, in the drinking water from birth, there was a dramatic delay in the onset of tumor growth ( approximately 6 weeks), and only 25% of DFMO-treated mice developed tumors by 15 weeks of age. All untreated K14-MEK mice developed tumors by 6 weeks of age. Treatment of tumor-bearing mice with DFMO reduced both tumor size and tumor number within several weeks. Tumor regression was the result of both inhibition of proliferation and increased apoptosis in tumors. The results establish ODC activation as an important component of the Raf/MEK/ERK pathway, and identify K14-MEK mice as a valuable model with which to study the regulation of ODC in ras carcinogenesis.