不同類型腫瘤的產(chǎn)生依賴于DNA損傷效應(yīng)、細(xì)胞周期關(guān)鍵點(diǎn)以及凋亡的特定蛋白質(zhì)的突變,。(Credit: Image courtesy of Institute for Research in Biomedicine-IRB)
近日,，來自巴塞羅那生物醫(yī)藥研究所（IRBB）和斯隆凱特琳癌癥研究中心（MSKCC）的研究者揭示了癌癥起源新的研究信息，這項研究刊登在了國際著名雜志PNAS上,。文章中,，研究者表示癌癥最初的形式及攻擊力取決于機(jī)體防衛(wèi)細(xì)胞完整性很多過程的缺失的結(jié)合，小鼠實驗中,，研究者發(fā)現(xiàn)高度染色體不穩(wěn)定性以及程序性細(xì)胞死亡的缺失的小鼠很少發(fā)展為腫瘤,。
腫瘤是否發(fā)展依賴于細(xì)胞周期中細(xì)胞損傷發(fā)生的時間，這項研究中,，研究者H.Stracker表示,，損傷應(yīng)答可以促使腫瘤發(fā)生。
研究者使用癌癥關(guān)鍵修復(fù)基因突變的小鼠,，下一步,，他們將這些小鼠和其它有細(xì)胞周期關(guān)鍵點(diǎn)或者凋亡相關(guān)突變的小鼠結(jié)合在一起，直到組合足以啟動腫瘤發(fā)生或者產(chǎn)生某些類型的腫瘤,，這就好比是解構(gòu)癌癥以發(fā)現(xiàn)效應(yīng)因子,。分裂細(xì)胞在DNA復(fù)制期間存在一系列的關(guān)鍵點(diǎn)，復(fù)制就在這些合適的關(guān)鍵點(diǎn)來發(fā)生。如果細(xì)胞在某些階段檢測到了錯誤,，細(xì)胞生長就會延遲而且高度復(fù)雜的DNA修復(fù)過程就會被激發(fā),。如果修復(fù)機(jī)能缺失并且細(xì)胞內(nèi)積累了很多基因組錯誤，監(jiān)控蛋白便會介入,，如腫瘤抑制子p53,。這樣一來，蛋白質(zhì)可以激活程序性細(xì)胞死亡,，或者細(xì)胞周期停滯,。
這項研究中，研究者表示基因組的不穩(wěn)定并不足以形成腫瘤,，他們需要更深入地研究不同種類癌癥的起源,，盡管大海撈針很困難,，但是研究者們會努力去深入研究他們所發(fā)現(xiàn)的結(jié)果。引發(fā)不同類型癌癥的關(guān)鍵角色的缺失將對于發(fā)明出新的診斷工具以及特殊的治療方法尤為重要,。（生物谷Bioon.com）
編譯自：New Clues About the Origin of Cancer
編譯者：天使托
doi:10.1073/pnas.1120476109
PMC:
PMID:
Cell cycle- and DNA repair pathway-specific effects of apoptosis on tumor suppression
Steven S. Fostera, Saurav Dea, Linda K. Johnsonb, John H. J. Petrinia,1, and Travis H. Strackera,c,1
The DNA damage response comprises DNA repair, cell-cycle checkpoint control, and DNA damage-induced apoptosis that collectively promote genomic integrity and suppress tumorigenesis. Previously, we have shown that the Chk2 kinase functions independently of the Mre11 complex (Mre11, Rad50, and Nbs1) and ATM in apoptosis and suppresses tumorigenesis resulting from hypomorphic alleles of Mre11 or Nbs1. Based on this work, we have proposed that Chk2 limits the oncogenic potential of replication-associated DNA damage. Here we further address the role of Chk2 and damage-induced apoptosis in suppressing the oncogenic potential of chromosome breaks. We show that loss of Chk2 or a mutation in p53 (R172P), which selectively impairs its function in apoptosis, rescued the lethality of mice lacking Lig4, a ligase required for nonhomologous end-joining (NHEJ) repair of DNA double-strand breaks in G0/G1. In contrast to Lig4−/−p53−/− mice, Lig4−/−Chk2−/− and Lig4−/−p53R172P/R172P mice were not prone to organ-specific, rapid tumorigenesis. Although the severe NHEJ deficiency of Lig4−/− was a less potent initiator of tumorigenesis in the p53R172P/R172P and Chk2−/− backgrounds, where p53 cell-cycle functions are largely intact, even mild defects in the intra-S and G2/M checkpoints caused by mutations in Nbs1 are sufficient to influence malignancy in p53R172P/R172P mice. We conclude that the oncogenic potential of double-strand breaks resulting from NHEJ deficiency is highly restricted by nonapoptotic functions of p53, such as the G1/S checkpoint or senescence, suggesting that the particular facets of the DNA damage response required for tumor suppression are dictated by the proliferative status of the tumor-initiating cell.
