Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA.
Oncogene. 2010 Feb 18;29(7):1017-30. doi: 10.1038/onc.2009.411. Epub 2009 Nov 30.
Ebp1, an ErbB3 receptor-binding protein, inhibits cell proliferation and acts as a putative tumor suppressor. Ebp1 translocates into the nucleus and functions as a transcription co-repressor for E2F-1. Here, we show that Ebp1 p42 isoform can be sumoylated on both K93 and K298 residues, which mediate its nuclear translocation and are required for its anti-proliferative activity. We find that translocation in liposarcoma (TLS)/FUS, an RNA-binding nuclear protein that is involved in pre-mRNA processing and nucleocytoplasmic shuttling, has Sumo1 E3 ligase activity for Ebp1 p42. Ebp1 directly binds TLS/FUS, which is regulated by genotoxic stress-triggered phosphorylation on Ebp1. Ebp1 sumoylation facilitates its nucleolar distribution and protein stability. Overexpression of TLS enhances Ebp1 sumoylation, whereas depletion of TLS abolishes Ebp1 sumoylation. Moreover, unsumoylated Ebp1 mutants fail to suppress E2F-1-regulated transcription, resulting in loss of its anti-proliferation activity. Hence, TLS-mediated sumoylation is required for Ebp1 transcriptional repressive activity.
Ebp1 是一种 ErbB3 受体结合蛋白，可抑制细胞增殖，是一种潜在的肿瘤抑制因子。Ebp1 可转位到细胞核中，并作为 E2F-1 的转录共抑制因子发挥作用。在这里，我们表明 Ebp1 p42 同种型可以在 K93 和 K298 残基上发生 SUMO 化，这介导了其核转位，并使其具有抗增殖活性。我们发现脂肪肉瘤（TLS）/FUS 作为一种参与前体 RNA 加工和核质穿梭的 RNA 结合核蛋白，具有 SUMO1 E3 连接酶活性，可作用于 Ebp1 p42。Ebp1 直接与 TLS/FUS 结合，后者受 Ebp1 磷酸化引发的遗传毒性应激调节。Ebp1 的 SUMO 化促进其在核仁中的分布和蛋白稳定性。TLS 的过表达增强了 Ebp1 的 SUMO 化，而 TLS 的消耗则消除了 Ebp1 的 SUMO 化。此外，非 SUMO 化的 Ebp1 突变体不能抑制 E2F-1 调节的转录，导致其抗增殖活性丧失。因此，TLS 介导的 SUMO 化对于 Ebp1 的转录抑制活性是必需的。
