What does Stat3 do?
What does Stat3 do?
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DOI：
10.1172/jci200215650
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发表时间：
2002-05-01
影响因子：
15.9
通讯作者：
Lee, CK
中科院分区：
文献类型：
--
作者：
Levy, DE;Lee, CK
Stat3在不同细胞中的表达(5)。例如，Stat3刺激B细胞增殖的部分机制是通过抑制凋亡，这是一种通过诱导抗凋亡基因Bcl-2介导的功能。相反，单核细胞中Stat3的激活会导致c-myc和c-myb的下调，并诱导junB和IRF-1，这是一种与分化和生长停滞一致的基因调控模式。同样，一组不同的stat3依赖基因在il -6刺激的肝细胞中上调，这些基因是急性期反应分泌蛋白的基因（20）。至少在细胞培养系统中，其他信号系统似乎也严重依赖Stat3。例如，在颗粒形成过程中，G-CSF受体信号传导导致Stat3的显著激活。此外，受体上的Stat3必需位点是g - csf驱动的增殖所必需的，显性负Stat3的表达会损害增殖（21）。HGF在上皮细胞的小管生长过程中激活Stat3（22）。IL-10对巨噬细胞的抗炎特性需要Stat3激活（23）。如何一个共同的转录因子激活一个独特的基因程序依赖于细胞类型是一个积极的研究领域。Stat3，像其他Stat蛋白一样（24），也与癌症有关（见Bromberg，这个透视系列，参考文献25；以及其中的参考文献）。随着Stat3在v- src转化的细胞中被组成性磷酸化的开创性发现（26），越来越多的证据表明，激活的Stat3在恶性转化过程中起着关键作用。激活的Stat3已经在多种实验性恶性肿瘤中被观察到，并且通过使用显性阴性抑制剂或反义寡核苷酸来消除其导致恶性表型的逆转。Stat3自身的组成型活性版本的表达可导致成纤维细胞转化，这表明Stat3是一种致癌基因。此外，许多小鼠和人类恶性肿瘤显示Stat3活化，包括许多头颈癌、乳腺癌、多发性骨髓瘤和其他血液系统恶性肿瘤。在这些情况下，Stat3被描述为主要介导生存功能，并且诱导诸如Bcl-2和Bcl-X等抗凋亡基因被认为是Stat3作用的靶点。
Stat3 in different cells (5). For instance, part of the mechanism by which Stat3 stimulates B cell proliferation is through inhibition of apoptosis, a function mediated by induction of the antiapoptotic gene Bcl-2. In contrast, activation of Stat3 in monocytic cells leads to downregulation of c-myc and c-myb and induction of junB and IRF-1, a pattern of gene regulation consistent with differentiation and growth arrest. Likewise, a different set of Stat3-dependent genes are upregulated in IL-6–stimulated hepatocytes, genes for the secreted proteins of the acute-phase response (20). Additional signaling systems also appear to rely heavily on Stat3, at least in cell culture systems. For instance, G-CSF receptor signaling during granulopoiesis leads to a striking activation of Stat3. Moreover, the Stat3 requirement site on the receptor is required for G-CSF–driven proliferation, and expression of dominant negative Stat3 impairs proliferation (21). HGF activates Stat3 during the process of tubule outgrowth in epithelial cells (22). IL-10 requires Stat3 activation for its anti-inflammatory properties on macrophages (23). How a common transcription factor activates a distinct gene program dependent on cell type is an area of active investigation. Stat3, like other Stat proteins (24), has also been implicated in cancer (see Bromberg, this Perspective series, ref. 25; and references therein). Following the seminal discovery that Stat3 is constitutively phosphorylated in v-Src–transformed cells (26), considerable evidence has accumulated suggesting a critical role for activated Stat3 during malignant transformation. Activated Stat3 has been observed in a variety of experimental malignancies, and its abrogation by use of dominant negative inhibitors or antisense oligonucleotides has led to reversal of the malignant phenotype. Expression of a constitutively active version of Stat3 on its own can lead to fibroblast transformation, suggesting that Stat3 is an oncogene. Moreover, numerous mouse and human malignancies have shown activated Stat3, including many head and neck cancers, mammary carcinomas, multiple myelomas, and other hematological malignancies. In these situations, Stat3 has been described as mediating largely a survival function, and induction of such antiapoptotic genes as Bcl-2 and Bcl-X has been suggested as a target of Stat3 action.