AP1 factor inactivation in the suprabasal epidermis causes increased epidermal hyperproliferation and hyperkeratosis but reduced carcinogen-dependent tumor formation.
AP1 factor inactivation in the suprabasal epidermis causes increased epidermal hyperproliferation and hyperkeratosis but reduced carcinogen-dependent tumor formation.
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DOI：
10.1038/onc.2010.315
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发表时间：
2010-11-04
期刊：
影响因子：
8
通讯作者：
Eckert, R. L.
中科院分区：
文献类型：
--
作者：
Rorke, E. A.;Adhikary, G.;Jans, R.;Crish, J. F.;Eckert, R. L.
AP1 （jun/fos）因子包括一系列转录调控因子（c-jun、junB、junD、c-fos、FosB、Fra-1和Fra-2），它们是表皮角质形成细胞存活和分化的关键控制者，也是癌症发展的重要驱动因素。在表皮分化过程中，每个成员都在确定的细胞层中表达，并且AP1因子调节竞争过程（即增殖、凋亡和分化），这使得理解这些因子在表皮中的作用变得复杂。我们已经提出AP1因子在基底表皮和上基底表皮中的功能不同。为了验证这一点，我们通过靶向表达显性阴性c-jun （TAM67）来灭活小鼠表皮基底上AP1因子的功能，从而灭活所有AP1因子的功能。这导致基底角化细胞增殖增加，分化延迟和广泛的角化过度。这些发现与先前的研究结果相反，表明基底层AP1因子失活不会扰乱休息的表皮。有趣的是，尽管存在广泛的角化细胞过度增生，但对致癌物质依赖性肿瘤诱导的易感性明显减弱。这些新的观察结果有力地表明，AP1因子在基底表皮和基底上表皮中具有不同的作用，证实了AP1因子的功能是正常终末分化所必需的，并表明AP1因子在正常表皮和癌症进展中发挥不同的作用。
AP1 (jun/fos) factors comprise a family of transcriptional regulators (c-jun, junB, junD, c-fos, FosB, Fra-1 and Fra-2) that are key controllers of epidermal keratinocyte survival and differentiation, and are important drivers of cancer development. Understanding the role of these factors in epidermis is complicated by the fact that each member is expressed in defined cell layers during epidermal differentiation, and because AP1 factors regulate competing processes (i.e., proliferation, apoptosis and differentiation). We have proposed that AP1 factors function differently in basal versus suprabasal epidermis. To test this, we inactivated suprabasal AP1 factor function in mouse epidermis by targeted expression of dominant-negative c-jun (TAM67) which inactivates function of all AP1 factors. This produces increased basal keratinocyte proliferation, delayed differentiation, and extensive hyperkeratosis. These findings contrast with previous studies showing that basal layer AP1 factor inactivation does not perturb resting epidermis. It is interesting that in spite of extensive keratinocyte hyperproliferation, susceptibility to carcinogen-dependent tumor induction is markedly attenuated. These novel observations strongly suggest that AP1 factors have distinct roles in the basal versus suprabasal epidermis, confirm that AP1 factor function is required for normal terminal differentiation, and suggest that AP1 factors play a different role in normal epidermis versus in cancer progression.
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