It's got you covered. NF-kappaB in the epidermis.
It's got you covered. NF-kappaB in the epidermis.
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DOI：
10.1083/jcb.149.5.999
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发表时间：
2000-05-29
期刊：
影响因子：
--
通讯作者：
Fuchs E
中科院分区：
文献类型：
--
作者：
Kaufman CK;Fuchs E
核因子κB （NF-κB）信号通路在最初被描述14年后，作为快速反应性基因调控的一个主要例子一直存在（Sen和Baltimore， 1986）。即使通过阐明趋同激活途径和分化下游效应物揭示了复杂性，NF-κB信号传导的广义方案在其逻辑上仍然是优雅的：(a)外部信号刺激激酶(s)，如NF-κB诱导激酶（NIK）， MEKK1， Akt或TBK1/NAK，其激活NF-κB蛋白激酶抑制剂（IKK）；(b) IKK随后磷酸化两个关键丝氨酸残基上的NF-κB蛋白抑制剂（i -κB），使i -κB泛素化并随后被26S蛋白酶体降解；(c) Rel/NF-κB二聚体转录因子先前通过与i -κB的关联被囚禁在细胞质中，现在可以自由进入细胞核，找到其DNA序列识别基序，并调节转录（综述于Mercurio和Manning, 1999； Ozes等人，1999；Pomerantz和Baltimore, 1999； Romashkova和Makarov, 1999； Tojima等人，2000）。对NF-κB信号的持续研究揭示了其在应激反应、细胞凋亡、细胞存活、肿瘤发生和发展中的作用。NF-κB的有效诱导剂也多种多样，包括促炎刺激，如肿瘤坏死因子α (TNFα)、细胞因子和白细胞介素1ß （IL-1ß）、细菌和病毒产物、促凋亡和坏死刺激，从紫外线和照射到氧自由基，以及最近的细胞存活因子，如神经营养因子（综述：Gerondakis等人，1998；Foo和Nolan, 1999； Li和Karin, 1999； Middleton等人，2000）。NF-κB最初被发现是免疫系统的一个关键调节因子，现在被认为是许多器官和细胞类型功能的重要参与者。在过去的几年中，越来越多令人信服的证据表明，NF-κB激活结果的多样性可能在很大程度上反映了细胞类型和细胞分化状态（Ozes等，1999；Romashkova和Makarov, 1999; Ernfors, 2000）。在皮肤中，NF-κB在表皮生物学中起着特别重要的作用。表皮的增殖细胞长期受到太阳有害紫外线的照射，可能依靠NF-κB的活化来保护和生存（Fisher et al., 1996; Qin et al., 1999; Seitz et al., 2000）。最近在小鼠中进行的功能获得或丧失的研究表明，表皮在平衡生长和分化方面也起着同样重要的作用。如果正确的话，这将增加NF-κB在信号通路中的另一个刺激功能。
Fourteen years after its initial description, the nuclear factor κB (NF-κB) signaling pathway endures as a prime example of rapidly responsive gene regulation (Sen and Baltimore, 1986). Even with the complexities revealed through the elucidation of converging activation pathways and diverging downstream effectors, a generalized scheme of NF-κB signaling remains elegant in its logic:(a) external signals stimulate a kinase (s), such as NF-κB–inducing kinase (NIK), MEKK1, Akt, or TBK1/NAK, which activates the inhibitor of NF-κB protein kinase (IKK);(b) IKK then phosphorylates the inhibitor of NF-κB protein (IκB) on two critical serine residues, which targets IκB for ubiquitination and subsequent degradation by the 26S proteasome;(c) previously held captive in the cytoplasm through its association with IκB, the Rel/NF-κB dimeric transcription factor is now free to enter the nucleus, find its DNA sequence recognition motifs, and regulate transcription (reviewed in Mercurio and Manning, 1999; Ozes et al., 1999; Pomerantz and Baltimore, 1999; Romashkova and Makarov, 1999; Tojima et al., 2000). The ongoing examination of NF-κB signaling has revealed its everexpanding role in stress responses, apoptosis, cell survival, oncogenesis, and development. The list of potent inducers of NF-κB is also diverse and includes proinflammatory stimuli such as tumor necrosis factor α (TNFα), cytokines and interleukin 1ß (IL-1ß), bacterial and viral products, pro-apoptotic and necrotic stimuli ranging from ultraviolet light and-irradiation to oxygen free radicals, and, most recently, cell survival factors, eg, neurotrophins (reviewed by Gerondakis et al., 1998; Foo and Nolan, 1999; Li and Karin, 1999; Middleton et al., 2000). While first discovered as a key regulatory factor of the immune system, NF-κB is now recognized as an important player in the functioning of many organs and cell types. In the past few years, compelling evidence has been accumulating to suggest that the diversity in the outcome of NF-κB activation may be largely a reflection of the cell type and differentiation state of the cell (Ozes et al., 1999; Romashkova and Makarov, 1999; Ernfors, 2000). In the skin, NF-κB plays a particularly central role in epidermal biology. Perpetually subjected to the harmful ultraviolet rays of the sun, the proliferative cells of the epidermis may rely on NF-κB activation for protection and survival (Fisher et al., 1996; Qin et al., 1999; Seitz et al., 2000). More recent gain or loss of function studies in mice suggest an equally important role in balancing growth and differentiation in the epidermis. If correct, this would add yet another provocative function for NF-κB in signaling pathways.
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