表觀遺傳調(diào)控因子Polycomb復(fù)合物蛋白（PcG）被認(rèn)為與多種癌癥的發(fā)生有著極大的相關(guān)性,。Rnf2作為polycomb復(fù)合物1（PRC1）中主要的E3連接酶,，在多種腫瘤組織中表達(dá)水平明顯上升,。Rnf2與腫瘤發(fā)生及發(fā)展有著怎樣的關(guān)系，至今一直是個沒有解決的問題,。
中科院遺傳發(fā)育所張建研究組以腫瘤細(xì)胞系及腫瘤組織為模型,，發(fā)現(xiàn)Rnf2能夠通過催化腫瘤抑制因子p53的泛素化促進(jìn)其降解。在多種細(xì)胞中對Rnf2的調(diào)控活性進(jìn)行檢測發(fā)現(xiàn),，Rnf2僅在某些細(xì)胞中調(diào)控p53的穩(wěn)定性,，如生殖細(xì)胞癌等。體外培養(yǎng)的生殖細(xì)胞腫瘤中對Rnf2進(jìn)行敲降后檢測到明顯的凋亡細(xì)胞,，而同時對p53進(jìn)行敲降能抑制凋亡發(fā)生,。此外，下調(diào)Rnf2表達(dá)能顯著抑制體外或體內(nèi)腫瘤細(xì)胞的生長,。對卵巢癌組織芯片中Rnf2的表達(dá)水平進(jìn)行分析更顯示了Rnf2的高表達(dá)與p53的下調(diào)具有相關(guān)性,。這些結(jié)果表明Rnf2作為一個新的p53泛素化連接酶,，通過在特定細(xì)胞中調(diào)控p53的蛋白穩(wěn)定性影響其功能,。這一發(fā)現(xiàn)也提示了Rnf2作為一個癌癥特異性治療靶點(diǎn)的可能性。
該研究結(jié)果于1月14日在線發(fā)表于PNAS (doi:10.1073/pnas.1211604110),。張建研究組博士研究生蘇文靜為第一作者,，該研究得到了中科院、科技部和國家自然科學(xué)基金委的資助,。(生物谷Bioon.com)
doi: 10.1073/pnas.1211604110
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RNF2/Ring1b negatively regulates p53 expression in selective cancer cell types to promote tumor development
Wen-jing Sua,b, Jun-shun Fanga, Feng Chenga,b, Chao Liua, Fang Zhoua, and Jian Zhanga,1
Large numbers of studies have focused on the posttranslational regulation of p53 activity. One of the best-known negative regulators for p53 is MDM2, an E3 ubiquitin ligase that promotes p53 degradation through proteasome degradation pathways. Additional E3 ligases have also been reported to negatively regulate p53. However, whether these E3 ligases have distinct/overlapping roles in the regulation of p53 is largely unknown. In this study, we identify RNF2 (ring finger protein 2) as an E3 ligase that targets p53 for degradation. The E3 ligase activity of RNF2 requires Bmi1 protein, a component of the polycomb group (PcG) complex. The up-regulation of p53 does not affect RNF2 expression. Unlike Mdm2, RNF2 only degrades p53 in selective cell lines, such as those from germ-cell tumors. The knockdown of RNF2 induces apoptosis, which can be rescued through the reduction of p53 expression. Moreover, the down-regulation of RNF2 expression in germ-cell tumors significantly reduces tumor cell growth, while the simultaneous down-regulation of both genes restores tumor cell growth in vitro and in tumor xenograft models. Furthermore, a reverse correlation between RNF2 and p53 expression was detected in human ovarian cancer tissues. Together, these results indicate that RNF2 is an E3 ligase for p53 degradation in selective cells, implicating RNF2 as a therapeutic target to restore tumor suppression through p53 in certain tumor cells.
