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腾讯登录PNAS：癌症起源的新线索
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<p align="center"><span style="font-family: 楷体_GB2312; font-size: x-small;">不同类型肿瘤的产生依赖于DNA损伤效应、细胞周期关键点以及凋亡的特定蛋白质的突变。(Credit: Image courtesy of Institute for Research in Biomedicine-IRB)</span></p>
近日，来自巴塞罗那生物医药研究所（IRBB）和斯隆凯特琳癌症研究中心（MSKCC）的研究者揭示了癌症起源新的研究信息，这项研究刊登在了国际著名杂志<em>PNAS</em>上。文章中，研究者表示癌症最初的形式及攻击力取决于机体防卫细胞完整性很多过程的缺失的结合，小鼠实验中，研究者发现高度染色体不稳定性以及程序性细胞死亡的缺失的小鼠很少发展为肿瘤。
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肿瘤是否发展依赖于细胞周期中细胞损伤发生的时间，这项研究中，研究者H.Stracker表示，损伤应答可以促使肿瘤发生。
研究者使用癌症关键修复基因突变的小鼠，下一步，他们将这些小鼠和其它有细胞周期关键点或者凋亡相关突变的小鼠结合在一起，直到组合足以启动肿瘤发生或者产生某些类型的肿瘤，这就好比是解构癌症以发现效应因子。分裂细胞在DNA复制期间存在一系列的关键点，复制就在这些合适的关键点来发生。如果细胞在某些阶段检测到了错误，细胞生长就会延迟而且高度复杂的DNA修复过程就会被激发。如果修复机能缺失并且细胞内积累了很多基因组错误，监控蛋白便会介入，如肿瘤抑制子p53。这样一来，蛋白质可以激活程序性细胞死亡，或者细胞周期停滞。
这项研究中，研究者表示基因组的不稳定并不足以形成肿瘤，他们需要更深入地研究不同种类癌症的起源，尽管大海捞针很困难，但是研究者们会努力去深入研究他们所发现的结果。引发不同类型癌症的关键角色的缺失将对于发明出新的诊断工具以及特殊的治疗方法尤为重要。<img src="http://www.bioon.com/biology/UploadFiles/201206/2012060815553550.jpg" alt="" width="113" height="149" border="0" />
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<a title="" href="http://dx.doi.org/doi:10.1073/pnas.1120476109" target="_blank">doi:10.1073/pnas.1120476109</a>
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<br/><strong>Cell cycle- and DNA repair pathway-specific effects of apoptosis on tumor suppression</strong><br/>
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.
<br/>来源：生物谷
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<p align="center"><img src="http://www.bioon.com/biology/UploadFiles/201206/2012060815524088.jpg" alt="" width="800" height="280" border="0" /></p>
<div id="ztload"> </div>
<p align="center"><span style="font-family: 楷体_GB2312; font-size: x-small;">不同类型肿瘤的产生依赖于DNA损伤效应、细胞周期关键点以及凋亡的特定蛋白质的突变。(Credit: Image courtesy of Institute for Research in Biomedicine-IRB)</span></p>
近日，来自巴塞罗那生物医药研究所（IRBB）和斯隆凯特琳癌症研究中心（MSKCC）的研究者揭示了癌症起源新的研究信息，这项研究刊登在了国际著名杂志<em>PNAS</em>上。文章中，研究者表示癌症最初的形式及攻击力取决于机体防卫细胞完整性很多过程的缺失的结合，小鼠实验中，研究者发现高度染色体不稳定性以及程序性细胞死亡的缺失的小鼠很少发展为肿瘤。
<!--more-->
肿瘤是否发展依赖于细胞周期中细胞损伤发生的时间，这项研究中，研究者H.Stracker表示，损伤应答可以促使肿瘤发生。
研究者使用癌症关键修复基因突变的小鼠，下一步，他们将这些小鼠和其它有细胞周期关键点或者凋亡相关突变的小鼠结合在一起，直到组合足以启动肿瘤发生或者产生某些类型的肿瘤，这就好比是解构癌症以发现效应因子。分裂细胞在DNA复制期间存在一系列的关键点，复制就在这些合适的关键点来发生。如果细胞在某些阶段检测到了错误，细胞生长就会延迟而且高度复杂的DNA修复过程就会被激发。如果修复机能缺失并且细胞内积累了很多基因组错误，监控蛋白便会介入，如肿瘤抑制子p53。这样一来，蛋白质可以激活程序性细胞死亡，或者细胞周期停滞。
这项研究中，研究者表示基因组的不稳定并不足以形成肿瘤，他们需要更深入地研究不同种类癌症的起源，尽管大海捞针很困难，但是研究者们会努力去深入研究他们所发现的结果。引发不同类型癌症的关键角色的缺失将对于发明出新的诊断工具以及特殊的治疗方法尤为重要。<img src="http://www.bioon.com/biology/UploadFiles/201206/2012060815553550.jpg" alt="" width="113" height="149" border="0" />
<div id="ztload">
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<a title="" href="http://dx.doi.org/doi:10.1073/pnas.1120476109" target="_blank">doi:10.1073/pnas.1120476109</a>
PMC:
PMID:
</div>
<div>
<br/><strong>Cell cycle- and DNA repair pathway-specific effects of apoptosis on tumor suppression</strong><br/>
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.
<br/>来源：生物谷
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