Smith P D, Crompton M R
Cell Biology and Experimental Pathology, Haddow Laboratories, Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey SM2 5NG, U.K.
Biochem J. 1998 Apr 15;331 ( Pt 2)(Pt 2):381-5. doi: 10.1042/bj3310381.
Transgenic mouse models of mammary tumorigenesis and analyses of human breast tumour samples have indicated a role for Src proteins in the tumorigenic process. The downstream effectors of Src function in mammary epithelial cells are less well understood. STAT proteins constitute a family of transcription factors whose activation by cytokine and non-cytokine receptors leads to tyrosine phosphorylation, dimerization and translocation from the cytoplasm to the nucleus. In the nucleus they activate the transcription of specific genes by binding to consensus DNA elements. STATs 1 and 3 can be activated by both cytokine and non-cytokine receptors, and bind as homodimers or heterodimers to viral simian sarcoma virus (sis)-inducible elements such as that found in the c-fos promoter. Here we report that one of the downstream effectors of Src function in mammary epithelial cells is STAT3. We demonstrate that v-src expression in mammary epithelial cells induces Tyr-705 phosphorylation, nuclear translocation and DNA binding of STAT3. Furthermore, we demonstrate that v-src can induce STAT3-dependent transcription. These observations are the first direct evidence that v-src can regulate transcription through the activation of STAT proteins, and add a further level of complexity to the understanding of the mode of action of v-src.
乳腺肿瘤发生的转基因小鼠模型以及对人类乳腺肿瘤样本的分析表明，Src蛋白在肿瘤发生过程中发挥作用。Src在乳腺上皮细胞中的下游效应器尚不太清楚。STAT蛋白构成一类转录因子，细胞因子和非细胞因子受体对其激活会导致酪氨酸磷酸化、二聚化以及从细胞质转运至细胞核。在细胞核中，它们通过与共有DNA元件结合来激活特定基因的转录。STAT1和STAT3可被细胞因子和非细胞因子受体激活，并以同二聚体或异二聚体形式结合至病毒猿猴肉瘤病毒（sis）诱导元件，如在c-fos启动子中发现的元件。在此我们报告，Src在乳腺上皮细胞中的下游效应器之一是STAT3。我们证明，乳腺上皮细胞中v-src的表达可诱导STAT3的Tyr-705磷酸化、核转运及DNA结合。此外，我们证明v-src可诱导STAT3依赖的转录。这些观察结果是v-src可通过激活STAT蛋白来调节转录的首个直接证据，并为理解v-src的作用模式增添了进一步的复杂性。
