Small Molecule Inhibitors of Signal Transducer and Activator of Transcription 3 (Stat3) Protein
Small Molecule Inhibitors of Signal Transducer and Activator of Transcription 3 (Stat3) Protein
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DOI：
10.1021/jm300207s
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发表时间：
2012-08-09
影响因子：
7.3
通讯作者：
Neamati, Nouri
中科院分区：
文献类型：
--
作者：
Debnath, Bikash;Xu, Shili;Neamati, Nouri
Stat 3由两个研究小组独立发现和研究，并于1994年描述。Akira等人从小鼠肝细胞核提取物中纯化并克隆了Stat 3，将其命名为急性期反应因子（APRF），并将Stat 3鉴定为选择性结合急性期基因启动子内IL-6反应元件的DNA结合因子。3 Zhong等人发现Stat 3是一种响应表皮生长因子的DNA结合蛋白。4从那时起，多种Stat 3亚型被鉴定，包括长型Stat 3 α、截短型Stat 3 β和Stat 3 γ，以及一种推定的新型Stat 3 δ，5均来源于位于染色体17 q21内的单个基因，通过转录本3′端的选择性剪接。5 Stat 3 α（p92）是一个由770个氨基酸组成的蛋白质，是Stat 3在大多数细胞类型中的主要表达形式。6 Stat 3 β（p83）是Stat 3 α的一种选择性剪接RNA形式，其中反式激活结构域的55个C末端氨基酸被7个不同的氨基酸取代。Stat 3 β通常被认为是显性阴性Stat 3亚型7，直到最近的体内实验证据表明Stat 3 β挽救了Stat 3无效突变的胚胎致死性，并且能够单独激活Stat 3靶基因的表达。8.与Stat 3 α和Stat 3 β相比，Stat 3 γ和Stat 3 δ的生理作用不太清楚。Stat 3 γ（p72）是Stat 3 α的另一种C-末端截短形式，其通过有限的蛋白水解而在术后衍生。Stat 3 γ主要在终末分化的中性粒细胞中活化。9 Stat 3 δ低水平存在，并随细胞分化而降低。5本文综述了Stat 3的信号通路，Stat 3在不同疾病中的作用以及Stat 3在干细胞维持中的作用，以及自2006年以来Stat 3抑制剂的设计、发现和开发的进展。
Stat3 was independently discovered and studied by two research groups and described in 1994. Akira et al. purified and cloned Stat3 from mouse liver nuclear extracts, named it as acute-phase response factor (APRF), and also identified Stat3 as a DNA-binding factor that selectively binds to the IL-6-responsive element within the acute-phase gene promoter. 3 Zhong et al. discovered Stat3 as a DNA-binding protein in response to epidermal growth factor. 4 Since then, multiple Stat3 isoforms have been identified, including the long form Stat3α, the truncated forms Stat3β and Stat3γ, and a putative novel form Stat3δ, 5 all derived from a single gene located within chromosome 17q21 via alternative splicing of the transcript’s 3′ end. 5 Stat3α (p92), a 770 amino acid protein, is the predominantly expressed form of Stat3 in most cell types. 6 Stat3β (p83) is an alternatively spliced RNA form of Stat3α, in which the 55 C-terminal amino acids of the transactivation domain are replaced by seven distinct amino acids. Stat3β was generally regarded as a dominant negative Stat3 isoform 7 until recent in vivo experimental evidence showed that Stat3β rescued the embryonic lethality of a Stat3-null mutation and was capable by itself of activating the expression of Stat3 target genes. 8 Compared with Stat3α and Stat3β, the physiologic roles of Stat3γ and Stat3δ are less clear. Stat3γ (p72) is another C-terminal truncated form of Stat3α derived post-translationally through limited proteolysis. Stat3γ is primarily activated in terminally differentiated neutrophils. 9 Stat3δ exists at low levels and decreases with cell differentiation. 5 In this review, we summarize the signaling pathways of Stat3, its role in different diseases as well as in stem cell maintenance, and the progress in the design, discovery, and development of Stat3 inhibitors since 2006.