Divergent roles of STAT1 and STAT5 in malignancy as revealed by gene disruptions in mice
Divergent roles of STAT1 and STAT5 in malignancy as revealed by gene disruptions in mice
复制标题
DOI：
10.1038/sj.onc.1203480
复制
发表时间：
2000-05-15
期刊：
影响因子：
8
通讯作者：
Gilliland, DG
中科院分区：
文献类型：
--
作者：
Levy, DE;Gilliland, DG
Stat蛋白是细胞因子和生长因子受体下游酪氨酸磷酸化激活的潜在转录因子，参与多种细胞生长调节途径。在各种转化细胞系和原发性恶性组织中也观察到组成性磷酸化，表明Stat蛋白活化可能有助于转化表型。一种区分恶性肿瘤中的致病作用（与旁观者磷酸化相反）与伴随转化的增加的酪氨酸磷酸化的方法是在转基因小鼠中使用靶向基因破坏来研究在不存在特定Stat蛋白的情况下的细胞生长和恶性肿瘤。这些研究表明，Stat1主要介导生长抑制信号并有助于肿瘤的宿主排斥，并且其在转化细胞中的活化对于恶性肿瘤不是必需的。Stat5的激活对于恶性转化可能是必要的和充分的，并且已经鉴定了单个Stat5靶基因，其对于增强的增殖是关键的。尽管如此，一些恶性肿瘤的特征是组成性磷酸化的Stat5不改变的StatS蛋白的损失。它在这些情况下的作用可能是多余的，与其他转化事件本身足以引起疾病，使酪氨酸磷酸化的Stat5在这些转化细胞中不必要的。
Stat proteins are latent transcription factors activated by tyrosine phosphorylation downstream of cytokine and growth factor receptors and have been implicated in a variety of cell growth regulatory pathways. Constitutive phosphorylation has also been observed in various transformed cell line and in primary malignant tissue, suggesting that Stat protein activation may contribute to the transformed phenotype. One method to distinguish between a causative role in malignancy as opposed to bystander phosphorylation from the increased tyrosine phosphorylation that accompanies transformation is to investigate cell growth and malignancy in the absence of particular Stat proteins using targeted gene disruptions in transgenic mice, Such studies show that Stat1 primarily mediates growth inhibitory signals and contributes to the host rejection of tumors, and that its activation in transformed cells is not necessary for malignancy. Activation of Stat5 can be both necessary and sufficient for malignant transformation, and single Stat5-target genes have been identified that are critical for heightened proliferation. Nonetheless, some malignancies that are characterized by constitutively phosphorylated Stat5 are not altered by the loss of StatS protein. Its role in these cases may be redundant with other transforming events that are in themselves sufficient to cause disease, rendering tyrosine phosphorylation of Stat5 unnecessary in these transformed cells.