生物谷報(bào)道：細(xì)胞產(chǎn)生不可修復(fù)的DNA損傷后通常會(huì)程序性死亡,，或稱凋亡,。然而在腫瘤細(xì)胞中這一機(jī)制失去作用,，所以它能夠肆意增殖,，拒絕接受“自殺”的命令。德國(guó)科學(xué)家近日發(fā)現(xiàn)了其中的可能原因——腫瘤細(xì)胞會(huì)降解一種能觸發(fā)凋亡的蛋白,。抑制這種蛋白的降解能夠使凋亡機(jī)制恢復(fù)作用,，并將提升放療和化療的效力。相關(guān)論文發(fā)表在《自然—細(xì)胞生物學(xué)》（Nature Cell Biology）上,。
嚴(yán)重DNA損傷后觸發(fā)凋亡的其中一類蛋白是HIPK2分子。德國(guó)癌癥研究中心的Thomas Hofmann和同事研究發(fā)現(xiàn),，HIPK2不斷在健康細(xì)胞中產(chǎn)生,，但一種名為Siah-1的酶將它標(biāo)記為“垃圾”，所以它又立刻被降解,。
輕微損傷的細(xì)胞會(huì)進(jìn)入一種低級(jí)警戒狀態(tài)——短時(shí)間內(nèi)抑制HIPK2的降解,。一旦損傷得到修復(fù)，細(xì)胞會(huì)立即恢復(fù)對(duì)HIPK2的降解,。只有在嚴(yán)重?fù)p傷（比如DNA雙鏈均遭破壞）的細(xì)胞中,，HIPK2的降解才被永久性地抑制。結(jié)果HIPK2不斷積累,，觸發(fā)凋亡,，細(xì)胞自殺。
研究人員推測(cè),，這可能就是放療和化療有時(shí)失效的原因,。這兩種治療方法都會(huì)嚴(yán)重?fù)p傷腫瘤細(xì)胞，最終導(dǎo)致它們的程序性死亡,。Thomas Hofmann說(shuō)：“如果有抵抗發(fā)生,，經(jīng)常是由于腫瘤細(xì)胞‘拒絕’執(zhí)行自殺的命令。”
研究人員在實(shí)驗(yàn)中抑制了Siah-1酶,，結(jié)果發(fā)現(xiàn),，即使在輕微損傷的細(xì)胞中,，HIPK2也能夠積聚，凋亡也被觸發(fā),。Hofmann推測(cè),，“癌醫(yī)學(xué)將可能利用這一發(fā)現(xiàn)。比如,，我們可以將Siah-1抑制劑與放療或化療結(jié)合使用,，從而將細(xì)胞拉回到凋亡機(jī)制中來(lái)。”（生物谷www.bioon.com）
生物谷推薦原始出處：
Nature Cell Biology,，doi:10.1038/ncb1743,，Melanie Winter，Thomas G. Hofmann
Control of HIPK2 stability by ubiquitin ligase Siah-1 and checkpoint kinases ATM and ATR
Melanie Winter1,2, Dirk Sombroek1,2, Ilka Dauth1, Jutta Moehlenbrink1, Karin Scheuermann1, Johanna Crone1 & Thomas G. Hofmann1
Abstract
The tumour suppressor HIPK2 is an important regulator of cell death induced by DNA damage, but how its activity is regulated remains largely unclear. Here we demonstrate that HIPK2 is an unstable protein that colocalizes and interacts with the E3 ubiquitin ligase Siah-1 in unstressed cells. Siah-1 knockdown increases HIPK2 stability and steady-state levels, whereas Siah-1 expression facilitates HIPK2 polyubiquitination, degradation and thereby inactivation. During recovery from sublethal DNA damage, HIPK2, which is stabilized on DNA damage, is degraded through a Siah-1-dependent, p53-controlled pathway. Downregulation of Siah-1 inhibits HIPK2 degradation and recovery from damage, driving the cells into apoptosis. We have also demonstrated that DNA damage triggers disruption of the HIPK2–Siah-1 complex, resulting in HIPK2 stabilization and activation. Disruption of the HIPK2–Siah-1 complex is mediated by the ATM/ATR pathway and involves ATM/ATR-dependent phosphorylation of Siah-1 at Ser 19. Our results provide a molecular framework for HIPK2 regulation in unstressed and damaged cells.
