Stat proteins and oncogenesis
Stat proteins and oncogenesis
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DOI：
10.1172/jci200215617
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发表时间：
2002-05-01
影响因子：
15.9
通讯作者：
Bromberg, J
中科院分区：
文献类型：
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作者：
Bromberg, J
在原发性癌症和肿瘤衍生细胞系中持续酪氨酸磷酸化（即持续活化）STAT蛋白的第一份报告是在发现STAT后不久出现的（表1）。随后的工作表明，在许多肿瘤衍生的细胞系中，STAT，特别是STAT 3，是维持转化表型所必需的。STAT 5通常也被发现在某些恶性肿瘤中被组成性激活，特别是白血病和淋巴瘤（表1）。引起JAK 2、PDGF-R或ABL信号传导增强或不受限制的融合蛋白的表达可导致STAT 5的组成性激活。在小鼠模型中的工作表明，bcr-abl和v-abl诱导的白血病不需要Stat 5（17），但这种蛋白质是由TEL-JAK融合导致的骨髓增生性疾病所必需的（18）。Stat 3缺陷型鼠T细胞、乳腺上皮细胞、巨噬细胞、成纤维细胞和角质形成细胞是有活力的、相对正常的细胞，具有通常涉及细胞凋亡调节的细微缺陷（19）。因此，在这几个实例中，Stat 3对于正常细胞的活力不是必需的。相比之下，许多含有组成性激活的STAT 3的癌症衍生的细胞系依赖于该蛋白质，并且当用针对STAT 3的反义或显性负性构建体处理时经历生长停滞或凋亡。STAT 3信号传导是致癌的直接证据来自于STAT 3的自发二聚突变形式STAT 3-C的工作，其不需要酪氨酸磷酸化被激活，但能够转化成纤维细胞（20）。没有已知的天然存在的STAT 3突变导致其组成性激活和随后的细胞转化。在所有自然发生的肿瘤和癌基因转化的细胞中，STAT 3激活通常依赖于失调的生长因子受体酪氨酸激酶或其相关的Jak激酶。因此，在与异常调节的Ret受体酪氨酸激酶相关的甲状腺癌的情况下，Schuringa et al. (21)已经发现通过Ret的转化需要STAT 3的磷酸化和活化。类似地，显性负性STAT 3的表达消除了与受体c-kit中的激活突变相关的急性髓性白血病（AML）和胃肠道基质细胞肿瘤（GIST）中的细胞转化（22）。STAT 3在霍奇金病中也被持续激活，其中AG 490，JAK 2和STAT 3磷酸化的抑制剂，可用于抑制肿瘤生长（23）。在原发性前列腺癌标本和前列腺癌衍生细胞系中，同样地，STAT 3被激活，并且STAT 3的反义的引入引起肿瘤细胞凋亡（24，25）。最后，在罕见的恶性大颗粒淋巴细胞白血病中发现持续激活的STAT 3和JAK 2;阻断STAT 3表达或功能的治疗通过上调促凋亡蛋白Fas和下调抗凋亡Mcl-1而引起癌细胞死亡（26，27）。针对STAT 3的反义试剂和显性负性构建体，以及Jak抑制剂如AG 490，因此具有肿瘤特异性生长抑制的前景，并且似乎对一系列癌细胞有用（表1）。此外，Jove及其同事最近开发了一种阻断STAT 3功能的新方法，使用与蛋白转导结构域相连的磷酸肽（28）。该肽
The first reports of persistently tyrosine-phosphorylated (that is, persistently activated) STAT proteins in primary cancers and tumor-derived cell lines came shortly after the discovery of the STATs (Table 1). Subsequent work showed that, in a number of tumorderived cell lines, the STATs, particularly STAT3, are required to maintain a transformed phenotype. STAT5 is also commonly found to be constitutively activated in certain malignancies, especially leukemias and lymphomas (Table 1). The expression of fusion proteins that cause heightened or unrestrained JAK2, PDGF-R, or ABL signaling can lead to the constitutive activation of STAT5. Work in murine models shows that bcr-abl–and v-abl–induced leukemias do not require Stat5 (17) but that this protein is required for a myeloproliferative disorder that results from a TEL-JAK fusion (18). Stat3-deficient murine T cells, mammary epithelial cells, macrophages, fibroblasts, and keratinocytes are viable, relatively normal cells with subtle defects typically involving the regulation of apoptosis (19). Thus, in these few examples, Stat3 is not essential for viability of normal cells. In contrast, many cancer-derived cell lines that contain consitutively activated STAT3 are dependent on this protein and undergo growth arrest or apoptosis when treated with antisense or dominant negative constructs directed at STAT3. Direct evidence that STAT3 signaling is oncogenic comes from work with a spontaneously dimerizingmutant form of STAT3, STAT3-C, which does not require tyrosine phosphorylation to be activated yet is capable of transforming fibroblasts (20). There are no known naturally occurring mutations of STAT3 that lead to its constitutive activation and subsequent transformation of cells. In all naturally occurring tumors and in oncogene-transformed cells, STAT3 activation is typically dependent upon dysregulated growth factor receptor tyrosine kinases or their associated Jak kinases. Thus, in the case of thyroid cancers associated with an aberrantly regulated Ret receptor tyrosine kinase, Schuringa et al.(21) have found that transformation by Ret requires phosphorylation and activation of STAT3. Similarly, expression of a dominant negative STAT3 abrogates cellular transformation in the acute myelogenous leukemia (AML) and gastrointestinal stromal cell tumors (GISTs) associated with activating mutations in the receptor c-kit (22). STAT3 is also persistently activated in Hodgkin disease, where AG490, an inhibitor of JAK2 and STAT3 phosphorylation, can be used to inhibit tumor growth (23). In primary prostate cancer specimens and prostate cancer–derived cell lines, likewise, STAT3 is activated, and the introduction of antisense to STAT3 provokes tumor cell apoptosis (24, 25). Finally, persistently activated STAT3 and JAK2 are found in the rare malignancy large granular lymphocyte leukemia; treatments that block STAT3 expression or function cause cancer cell death by upregulating the proapoptotic protein Fas and downregulating the antiapoptotic Mcl-1 (26, 27).Antisense reagents and dominant negative constructs directed at STAT3, as well as Jak inhibitors such as AG490, thus hold the promise of tumor-specific growth inhibition and appear to be useful against a range of cancer cells (Table 1). In addition, Jove and colleagues recently developed a novel approach to blocking STAT3 function, using a phosphopeptide tethered to a protein transduction domain (28). This peptide