IkappaB kinase alpha (IKKalpha), one of the two catalytic subunits of the IKK complex involved in nuclear factor kappaB (NF-kappaB) activation, also functions as a molecular switch that controls epidermal differentiation. This unexpected function requires IKKalpha nuclear translocation but does not depend on its kinase activity, and is independent of NF-kappaB signalling. Ikkalpha(-/-) mice present with a hyperproliferative and undifferentiated epidermis characterized by complete absence of a granular layer and stratum corneum. Ikkalpha-deficient keratinocytes do not express terminal differentiation markers and continue to proliferate even when subjected to differentiation-inducing stimuli. This antiproliferative function of IKKalpha is also important for the suppression of squamous cell carcinogenesis. The exact mechanisms by which nuclear IKKalpha controls keratinocyte proliferation and differentiation remained mysterious for some time. Recent studies, however, have revealed that IKKalpha is a major cofactor in a TGFbeta-Smad2/3 signalling pathway that is Smad4 independent. This pathway controls cell cycle withdrawal during keratinocyte terminal differentiation. Although these are not the only functions of nuclear IKKalpha, this multifunctional protein is a key regulator of keratinocyte and epidermal differentiation and a critical suppressor of skin cancer.

译文

IkappaB激酶 α (IKKalpha),参与核因子kappaB (NF-kappaB) 激活的IKK复合物的两个催化亚基之一,也起着控制表皮分化的分子开关的作用。这种意外的功能需要IKKalpha核易位,但不依赖于其激酶活性,并且独立于NF-kappaB信号传导。Ikkalpha(-/-) 小鼠具有过度增殖和未分化的表皮,其特征是完全没有颗粒层和角质层。Ikkα 缺陷型角质形成细胞不表达终末分化标记,即使受到分化诱导刺激,也继续增殖。IKKalpha的这种抗增殖功能对于抑制鳞状细胞癌的发生也很重要。核IKKalpha控制角质形成细胞增殖和分化的确切机制在一段时间内仍然是神秘的。然而,最近的研究表明,IKKalpha是Smad4独立的TGFbeta-Smad2/3信号通路中的主要辅助因子。该途径控制角质形成细胞终末分化过程中的细胞周期退出。尽管这些不是核IKKalpha的唯一功能,但这种多功能蛋白是角质形成细胞和表皮分化的关键调节剂,也是皮肤癌的关键抑制剂。

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