Elevated levels of ornithine decarboxylase cooperate with Raf/ERK activation to convert normal keratinocytes into invasive malignant cells
Elevated levels of ornithine decarboxylase cooperate with Raf/ERK activation to convert normal keratinocytes into invasive malignant cells
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DOI：
10.1038/sj.onc.1209198
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发表时间：
2006-03-01
期刊：
影响因子：
8
通讯作者：
Gilmour, SK
中科院分区：
文献类型：
--
作者：
Hayes, CS;DeFeo, K;Gilmour, SK
鸟氨酸脱羧酶（ODC）过表达与活化的Ras偶联完全足以致癌转化原代角质形成细胞。为了确定Ras效应途径，代表在这种情况下，最小的基本贡献，以充分致癌转化，我们评估了不同的Ras效应突变体与过表达的ODC在体内气管异种移植试验上皮细胞侵袭的协同性。用逆转录病毒感染从K6/ODC转基因小鼠皮肤（表达增加的ODC）或从正常同窝小鼠皮肤分离的原代角质形成细胞，所述逆转录病毒产生活化的RasV 12或RasV 12的部分功能丧失效应子突变体，所述RasV 12的部分功能丧失效应子突变体选择性地仅诱导Raf/ERK、RalGDS或PI 3激酶信号传导途径。尽管表达完全活化的RasV 12的角质形成细胞在气管异种移植物中不具有侵袭性，但ODC过表达的角质形成细胞获得具有另外的RasV 12表达或Raf/ERK途径活化的侵袭性表型。独立于突变的ras，ODC水平升高激活原代角质形成细胞中的Akt/mTOR信号通路以及Rho/Rac通路。因此，Raf/ERK信号传导足以在正常角质形成细胞转化为侵袭性细胞中与增加的ODC活性合作。为了促进角质形成细胞的侵袭性，ODC水平升高可能通过Akt和Rho/Rac信号通路的激活与Raf/ERK协同作用。
Ornithine decarboxylase (ODC) overexpression coupled with activated Ras is fully sufficient to oncogenically transform primary keratinocytes. To determine the Ras effector pathways that represent the minimal essential contribution to full oncogenic transformation in this context, we evaluated the cooperativity of different Ras effector mutants with overexpressed ODC in an in vivo tracheal xenotransplantation assay for epithelial cell invasiveness. Primary keratinocytes, isolated from either K6/ODC transgenic mouse skin (expressing increased ODC) or from normal littermate skin were infected with retrovirus producing an activated RasV12 or partial loss-of-function effector mutants of RasV12 that selectively induce only the Raf/ERK, RalGDS, or the PI3-kinase signaling pathway. Whereas keratinocytes expressing a fully activated RasV12 are not invasive in tracheal xenotransplants, ODC-overexpressing keratinocytes acquire an invasive phenotype with additional expression of either RasV12 or activation of the Raf/ERK pathway. Independent of a mutated ras, elevated levels of ODC activate the Akt/mTOR signaling pathway as well as the Rho/Rac pathway in primary keratinocytes. Thus, Raf/ERK signaling is sufficient to cooperate with increased ODC activity in the conversion of normal keratinocytes to invasive cells. In order to promote invasiveness in keratinocytes, elevated levels of ODC may cooperate with Raf/ERK via activation of the Akt and Rho/Rac signaling pathway.