Liu Ling, McBride Kevin M, Reich Nancy C
Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, NY 11794-8691, USA.
Proc Natl Acad Sci U S A. 2005 Jun 7;102(23):8150-5. doi: 10.1073/pnas.0501643102. Epub 2005 May 26.
Signal transducer and activator of transcription (STAT)3 is a member of a family of DNA-binding factors that function to induce expression of responsive genes. STAT3 can act as an oncogene, and its function has been shown to be critical for cellular transformation by a number of oncogenic tyrosine kinases. The role of STAT3 as a DNA-binding transcription factor naturally depends on its ability to gain entrance to the nucleus. In this study, we provide evidence that STAT3 is distinct from previously characterized STAT molecules in that it dynamically shuttles between cytoplasmic and nuclear compartments and maintains prominent nuclear presence. Although tyrosine phosphorylation is required for STAT3 to bind to specific DNA target sites, nuclear import takes place constitutively and independently of tyrosine phosphorylation. We identify a region within the coiled-coil domain of the STAT3 molecule that is necessary for nuclear import and demonstrate that this region is critical for its recognition by specific import carrier importin-alpha3. RNA interference studies were used to verify the role and specificity of importin-alpha3 in STAT3 nuclear translocation. These results distinguish STAT3 cellular localization from other STAT molecules and identify a feature that may be targeted in the clinical intervention of STAT3-dependent neoplasia.
信号转导子和转录激活子（STAT）3是一类DNA结合因子家族的成员，其作用是诱导反应性基因的表达。STAT3可作为一种癌基因，并且已表明其功能对于多种致癌酪氨酸激酶引起的细胞转化至关重要。STAT3作为一种DNA结合转录因子的作用自然取决于其进入细胞核的能力。在本研究中，我们提供证据表明STAT3与先前表征的STAT分子不同，因为它在细胞质和细胞核区室之间动态穿梭，并在细胞核中持续存在。虽然STAT3结合特定DNA靶位点需要酪氨酸磷酸化，但核输入是组成性发生的，且独立于酪氨酸磷酸化。我们在STAT3分子的卷曲螺旋结构域内鉴定出一个对于核输入必需的区域，并证明该区域对于其被特定输入载体输入蛋白α3识别至关重要。RNA干扰研究用于验证输入蛋白α3在STAT3核转位中的作用及特异性。这些结果将STAT3的细胞定位与其他STAT分子区分开来，并确定了一个在STAT3依赖性肿瘤形成的临床干预中可能成为靶点的特征。
