Goueli Basem S, Janknecht Ralf
Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA.
Oncogene. 2003 Sep 11;22(39):8042-7. doi: 10.1038/sj.onc.1206847.
Upregulation of human telomerase reverse transcriptase (hTERT) transcription accounts for the immortalization of greater than 85% of all human tumor cells. However, the mechanism whereby hTERT expression is activated remains unresolved. Specifically, recent data challenging the role of Myc/Max in E-box-dependent activation of hTERT expression suggests that other E-box-binding proteins regulate hTERT transcription. Indeed, we now demonstrate that two such proteins, upstream stimulatory factor (USF) 1 and 2, readily associate with two E-boxes in the hTERT promoter in vitro and in vivo primarily as heterodimers, whereas Myc/Max does not. The avid binding of USF1/2 heterodimers to these E-boxes occurs in both hTERT-positive and -negative cells. In contrast, USF1/2 activates the hTERT promoter exclusively in hTERT-positive cells in a manner that is enhanced by the coactivator p300 and attenuated upon inhibiting p38-MAP kinase, a known modulator of USF activity. Collectively, our data indicate that USF binding to the hTERT promoter may be transcriptionally neutral, or even repressive, in nonimmortalized hTERT-negative somatic cells, but stimulatory in hTERT-positive cells where USF1/2 contributes to the acquisition and maintenance of immortality.
人类端粒酶逆转录酶（hTERT）转录的上调导致了超过85%的人类肿瘤细胞永生化。然而，hTERT表达被激活的机制仍未解决。具体而言，最近有数据对Myc/Max在hTERT表达的E盒依赖性激活中的作用提出质疑，这表明其他E盒结合蛋白调节hTERT转录。事实上，我们现在证明，两种这样的蛋白，即上游刺激因子（USF）1和2，在体外和体内主要以异二聚体的形式与hTERT启动子中的两个E盒容易结合，而Myc/Max则不然。USF1/2异二聚体对这些E盒的强烈结合在hTERT阳性和阴性细胞中均会发生。相比之下，USF1/2仅在hTERT阳性细胞中激活hTERT启动子，其激活方式会被共激活因子p300增强，而在抑制p38-MAP激酶（一种已知的USF活性调节剂）后减弱。总体而言，我们的数据表明，在未永生化的hTERT阴性体细胞中，USF与hTERT启动子的结合可能在转录上是中性的，甚至是抑制性的，但在hTERT阳性细胞中是刺激性 的，其中USF1/2有助于获得和维持永生化。
