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《Nature》封面故事（4.14）
两个小组在本期Nature上报告了他们的最新发现，这些发现有可能对我们关于癌症发育的观点产生重大影响。两个小组都对处在不同发育阶段的肿瘤（如膀胱癌、乳腺癌、结肠直肠癌、以及肺癌和皮肤癌等）进行了研究，寻找DNA受损响应的标志。而且，两个小组都发现，癌症发育早期阶段与一个主动的DNA受损响应和P53-依赖型细胞死亡有关。这表明，癌变事件所诱导的DNA受损响应是一种强有力的肿瘤抑制机制，而且也可以解释癌症前期病灶中P53突变的选择性压力。重要的是，DNA受损检查点的激发出现在染色体不稳定和恶变之前。本期封面所示为肺部增生中的53BP1病灶（绿颜色，指示DNA受损检查点的激发）。
DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis
JIRINA BARTKOVA1, ZUZANA HO EJ Í1,5, KAREN KOED2, ALWIN KRÄMER1, FREDERIC TORT1, KARSTEN ZIEGER2, PER GULDBERG1, MAXWELL SEHESTED3, JAHN M. NESLAND4, CLAUDIA LUKAS1, TORBEN ØRNTOFT2, JIRI LUKAS1 &
During the evolution of cancer, the incipient tumour experiences 'oncogenic stress', which evokes a counter-response to eliminate such hazardous cells. However, the nature of this stress remains elusive, as does the inducible anti-cancer barrier that elicits growth arrest or cell death. Here we show that in clinical specimens from different stages of human tumours of the urinary bladder, breast, lung and colon, the early precursor lesions (but not normal tissues) commonly express markers of an activated DNA damage response. These include phosphorylated kinases ATM and Chk2, and phosphorylated histone H2AX and p53. Similar checkpoint responses were induced in cultured cells upon expression of different oncogenes that deregulate DNA replication. Together with genetic analyses, including a genome-wide assessment of allelic imbalances, our data indicate that early in tumorigenesis (before genomic instability and malignant conversion), human cells activate an ATR/ATM-regulated DNA damage response network that delays or prevents cancer. Mutations compromising this checkpoint, including defects in the ATM–Chk2–p53 pathway, might allow cell proliferation, survival, increased genomic instability and tumour progression.
PARP酶在乳腺癌疗法中的作用
研究发现，BRCA1/2突变细胞（它们在DNA修复的同源重组通道中是有缺陷的）对PARP酶（参与碱基切补修复）的抑制极为敏感。这一发现为由BRCA突变引起的妇女乳腺癌的治疗找到一种新的、毒性小得多的治疗方法。因为PARP抑制因子对具有功能性同源重组的细胞没有作用，所以人们的希望是，这种新疗法只针对乳腺癌细胞。通过开发PARP抑制化疗方法，也许有可能研制成利用一种“合成毒药"效应的药物来，可以用这种药物来代替传统的非针对性细胞毒性抗癌疗法。
Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase
HELEN E. BRYANT1, NIKLAS SCHULTZ2, HUW D. THOMAS3, KAYAN M. PARKER1, DAN FLOWER1, ELENA LOPEZ1, SUZANNE KYLE3, MARK MEUTH1, NICOLA J. CURTIN3 & THOMAS HELLEDAY1,2
Poly(ADP-ribose) polymerase (PARP1) facilitates DNA repair by binding to DNA breaks and attracting DNA repair proteins to the site of damage. Nevertheless, PARP1-/- mice are viable, fertile and do not develop early onset tumours. Here, we show that PARP inhibitors trigger -H2AX and RAD51 foci formation. We propose that, in the absence of PARP1, spontaneous single-strand breaks collapse replication forks and trigger homologous recombination for repair. Furthermore, we show that BRCA2-deficient cells, as a result of their deficiency in homologous recombination, are acutely sensitive to PARP inhibitors, presumably because resultant collapsed replication forks are no longer repaired. Thus, PARP1 activity is essential in homologous recombination-deficient BRCA2 mutant cells. We exploit this requirement in order to kill BRCA2-deficient tumours by PARP inhibition alone. Treatment with PARP inhibitors is likely to be highly tumour specific, because only the tumours (which are BRCA2-/-) in BRCA2+/- patients are defective in homologous recombination. The use of an inhibitor of a DNA repair enzyme alone to selectively kill a tumour, in the absence of an exogenous DNA-damaging agent, represents a new concept in cancer treatment.
胚胎神经生长的引导机制
两个小组在本期Nature上发表的研究结果表明，胚胎神经依靠未曾料到的传感装置来引导它们的生长。这些发现可帮助科学家更好地了解大脑的神经系统。由“瞬时受体势”（TRP）蛋白形成的离子通道允许成年传感器官对温度、机械压力或味道等作出反应。现在，Gordon Wang 和 Mu-ming Poo在一个未曾料到的地方发现了TRP通道，这个地方就是胚胎神经的末梢，在那里，它们所控制的钙离子流允许神经朝向或远离引导分子生长。另一个小组发现，TRP通道在引导来自发育中的小脑的神经元的神经生长的过程中起类似作用。
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作者:admin@医学,生命科学 2011-03-10 17:11
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