The Mina and Everard Goodman Faculty of Life Science, Bar Ilan University, Ramat Gan 52900, Israel.
Mol Cancer Res. 2012 Sep;10(9):1169-77. doi: 10.1158/1541-7786.MCR-12-0331. Epub 2012 Jul 13.
The E2F family of transcription factors plays a pivotal role in the regulation of cell proliferation in higher eukaryotes and is a critical downstream target of the tumor suppressor pRB. The pRB/E2F pathway is defective in most human tumors, resulting in deregulated E2F activity that induces uncontrolled cell proliferation, a hallmark of tumor cells. The RNA-binding protein RBM38, also named RNPC1, induces cell-cycle arrest in G(1), at least in part, via binding to and stabilizing the mRNA of the cyclin-dependent kinase inhibitor p21. RBM38 levels are altered in human cancer. Generally, RBM38 is overexpressed in various tumors; however, RBM38 mRNA levels are reduced in some breast tumors due to increased methylation of its promoter region. We show here that expression of RBM38 is regulated by E2F1. Specifically, RBM38 mRNA and protein levels are elevated upon activation of either exogenous E2F1 or endogenous E2Fs. Moreover, endogenous E2F1 binds the human RBM38 promoter and E2F1 knockdown reduces RBM38 levels. Our data raise the possibility that E2F1 together with E2F1-regulated RBM38 constitute a negative feedback loop that modulates E2F1 activity. In support of this, inhibition of RBM38 expression increases E2F1-mediated cell-cycle progression. Moreover, in human ovarian cancer, high correlation between expression of E2F1 and RBM38 is associated with increased survival. Overall, our data identify RBM38 as novel transcriptional target of E2F1 that restricts E2F1-induced proliferation. Furthermore, this negative feedback loop seems to restrict tumor aggressiveness, thereby promoting survival of patients with cancer.
转录因子 E2F 家族在高等真核生物细胞增殖的调控中起着关键作用，是肿瘤抑制因子 pRB 的关键下游靶标。pRB/E2F 途径在大多数人类肿瘤中存在缺陷，导致 E2F 活性失控，从而引发不受控制的细胞增殖，这是肿瘤细胞的一个标志。RNA 结合蛋白 RBM38（也称为 RNPC1）至少部分通过与细胞周期蛋白依赖性激酶抑制剂 p21 的 mRNA 结合并稳定其，在 G1 期诱导细胞周期停滞。RBM38 水平在人类癌症中发生改变。通常，RBM38 在各种肿瘤中过表达；然而，由于其启动子区域的甲基化增加，一些乳腺癌中的 RBM38 mRNA 水平降低。我们在这里表明，RBM38 的表达受 E2F1 调节。具体来说，外源性 E2F1 或内源性 E2Fs 的激活会导致 RBM38 的 mRNA 和蛋白水平升高。此外，内源性 E2F1 结合人 RBM38 启动子，E2F1 敲低会降低 RBM38 水平。我们的数据提出了一种可能性，即 E2F1 与 E2F1 调节的 RBM38 一起构成了一个负反馈回路，调节 E2F1 活性。支持这一点的是，抑制 RBM38 的表达会增加 E2F1 介导的细胞周期进程。此外，在人类卵巢癌中，E2F1 和 RBM38 的表达高度相关与存活率增加有关。总体而言，我们的数据将 RBM38 确定为 E2F1 的新型转录靶标，限制了 E2F1 诱导的增殖。此外，这种负反馈回路似乎限制了肿瘤的侵袭性，从而促进了癌症患者的生存。
