Netrin-1 是一種分泌蛋白,，能促進(jìn)中樞神經(jīng)系統(tǒng)的軸束生長和細(xì)胞遷移。在多種癌癥中,，netrin - 1顯示出促癌活力,，這被認(rèn)為是由于netrin-1與其受體結(jié)合促進(jìn)了細(xì)胞的生存。
本研究發(fā)現(xiàn),，不同于全長分泌形式netrin-1,，某些癌細(xì)胞通過一個非主流啟動子啟動表達(dá)產(chǎn)生一個截短的，核仁內(nèi)形式的netrin-1（Delta-N netrin-1）,。因?yàn)楹巳识ㄎ恍盘栁挥谄漪然?，Delta-N netrin-1被定位于核仁內(nèi)。它與核仁蛋白相互作用,，影響核仁的超微結(jié)構(gòu),，并與核糖體基因的啟動子相互作用。
此外,，在體外實(shí)驗(yàn)中,，Delta-N netrin-1刺激細(xì)胞增殖。Delta-N netrin-1同時促進(jìn)體內(nèi)的腫瘤生長,。因此,，癌細(xì)胞不僅通過產(chǎn)生一個全長分泌形式的netrin-1，促進(jìn)細(xì)胞的存活,，也通過產(chǎn)生截短形式的netrin-1提高核糖體合成,，以刺激細(xì)胞增殖。(生物谷bioon.com)
doi:10.1016/j.cell.2011.10.017
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Nucleolar Localization of a Netrin-1 Isoform Enhances Tumor Cell Proliferation
Céline Delloye-Bourgeois1*, David Goldschneider1*, Andrea Paradisi1*, Gabriel Therizols2*, Stéphane Belin2, Sabine Hacot2, Manuel Rosa-Calatrava3, Jean-Yves Scoazec4, Jean-Jacques Diaz2, Agnès Bernet1, and Patrick Mehlen1
Netrin-1 displays proto-oncogenic activity in several cancers, which is thought to be due to the ability of this secreted cue to stimulate survival when bound to its receptors. We showed that in contrast to full-length, secreted netrin-1, some cancer cells produced a truncated intranuclear form of netrin-1 (N-netrin-1) through an alternative internal promoter. Because of a nucleolar localization signal located in its carboxyl terminus, N-netrin-1 was targeted to the nucleolus, where it interacted with nucleolar proteins, affected nucleolar ultrastructure, and interacted with the promoters of ribosomal genes. Moreover, N-netrin-1 stimulated cell proliferation in vitro and tumor growth in vivo. Thus, some cancer cells produce not only a full-length, secreted form of netrin-1 that promotes cell survival but also a truncated netrin-1 that stimulates cell proliferation, potentially by enhancing ribosome biogenesis.
