Sommer Stephanie, Cui Yukun, Brewer Gary, Fuqua Suzanne A W
Breast Center, Baylor College of Medicine and The Methodist Hospital, Houston, TX 77030, USA.
J Steroid Biochem Mol Biol. 2005 Nov;97(3):219-29. doi: 10.1016/j.jsbmb.2005.09.002.
c-Yes is a member of the c-Src family of tyrosine kinases and has been implicated in intracellular signaling, cell morphology, and adhesion. Changes in its expression have also been associated with the aggressiveness of human breast and colon cancer cells. In MDA-MB-231 human breast cancer cells, overexpression of the small heat shock protein 27 (hsp27) results in a downregulation of c-Yes levels, concomitant with increased in vitro invasiveness and in vivo metastatic behavior. Very little is known, however, about the mechanisms regulating c-Yes expression. Here, we demonstrate that hsp27-induced c-Yes downregulation is not due to a reduction in transcriptional activity. However, the 3'-untranslated region (3'-UTR) of the c-Yes gene may be involved in its own regulation, since this region affects heterologous reporter gene activity in transactivation assays. This down-regulatory effect maps to three adenine/uridine-rich elements (AREs) that bind to cellular HuR and AUF1 (hnRNP D), two ARE-binding proteins (ARE-BPs) implicated in accelerated mRNA degradation. Our results suggest that the c-Yes 3'-UTR contains at least three newly identified AREs which are bound specifically by ARE-BPs, and provide a structural basis for post-transcriptional regulation of c-Yes expression.
c-Yes是酪氨酸激酶c-Src家族的成员，与细胞内信号传导、细胞形态和黏附有关。其表达的变化也与人类乳腺癌和结肠癌细胞的侵袭性相关。在MDA-MB-231人乳腺癌细胞中，小热休克蛋白27（hsp27）的过表达导致c-Yes水平下调，同时体外侵袭性和体内转移行为增加。然而，关于调节c-Yes表达的机制知之甚少。在这里，我们证明hsp27诱导的c-Yes下调并非由于转录活性降低。然而，c-Yes基因的3'非翻译区（3'-UTR）可能参与其自身的调节，因为该区域在反式激活试验中影响异源报告基因的活性。这种下调作用定位于三个富含腺嘌呤/尿嘧啶的元件（AREs），它们与细胞HuR和AUF1（hnRNP D）结合，这两种ARE结合蛋白（ARE-BPs）与mRNA加速降解有关。我们的结果表明，c-Yes 3'-UTR包含至少三个新鉴定的AREs，它们被ARE-BPs特异性结合，并为c-Yes表达的转录后调节提供了结构基础。
