导致癌症的基因能够比之前人们认为的更强大而狡猾的方式搞破坏！研究人员已经证明，一种叫做JAK的基因能以一种意想不到的方式向着癌症前进。这种基因与人体的一种常见致癌基因有关。JAK能够在更广泛的水平上破坏生物体的DNA活动，阻碍胚胎发育早期的一个关键分子事件。
Rochester大学医学中心的研究救人员将这些发现发表在9月7日的Public Library of Science（PLoS）Genetics上。
研究人员将果蝇作为研究模型获得以上发现，而果蝇具有和人类相同的很多信号途径。通过对果蝇DNA进行操作并分析它们在发育过程种的体型，研究组获得了惊人发现：一种通常能抑制癌症的基因上DNA序列的突变所导致的促进癌症发生的效应能够从亲代传递给子代，及时这种突变本事并没有传递给后代。
在某些情况下，亲代中的一方携带这种突变就足够影响到后代，及时这种突变本身并没有传递给后代。
这项研究再一次证实，研究人员直到近年来才意识到的一个现实：尽管DNA编码一直被认为是唯一的一代代传递下去的遗传信息，但实际上还存在其他更为精妙的遗传物质——一种能够在代间传递的“分子记忆”。
研究人员通过对一种致癌基因JAK激酶基因进行研究，从而获得了这一发现。在人体中，一种与与JAK及其相似的生化系统对人体健康至关重要，但是它的信号似乎“乱窜”。该系统在淋巴瘤或白血病的发生过程中起到一定的作用。
JAK 激酶
JAK 激酶是酪氨酸激酶，其主要底物是称为STAT 的转录因子。有超过7 种STAT，每个都由特殊系列的JAK激酶磷酸化。磷酸化在JAK 与受体在质膜上结合时发生。一对JAK激酶与活化的受体作用，两者对保证途径的正常功能都很重要。例如，应答干扰素(Interferon)IFNγ的刺激同时需要JAK1和JAK2。
STAT 磷酸化导致同二聚体(Homodimer)和异二聚体(Heterodimer)的形成。二聚化的基础是一个亚基中SH2结构域与另一亚基中磷酸化酪氨酸相互作用。STAT二聚体进入核内，在有些情况下与其它蛋白质共同作用。它们结合到靶基因特异性识别元素上，从而激活靶基因转录。
一系列相关的细胞因子受体、JAK 激酶和 STAT转录因子，其特异性是如何获得的呢？许多受体能够激活同一个JAK，但激活不同的STAT，这使问题更尖锐化。特异性的控制在于多成分复合体的形成，包括受体、JAKs和STATs。STAT 直接与受体和JAK作用，每一STAT 的SH2结构域能识别某个受体上的结合位点，因此特异性的控制在于STAT。JAK-STAT途径的激活是瞬间的，其活性能被一个磷酸酶的作用终止。例如，红细胞生成素(Erythropoietin，血红细胞激素)与其受体结合激活途径。另一个成分的结合则使该途径终止。磷酸化酶SH-PTP1通过其SH2结构域结合到红细胞生成素受体的酪氨酸磷酸化位点，受体上这个位点可能由JAK2磷酸化。磷酸化酶随后磷酸化JAK2并终止相应的STAT的活性。这形成了一个简单的反馈回路：红细胞生成素受体激活JAK2，JAK2作用于受体的一个位点上，这个位点被磷酸化酶识别，反过来作用于JAK2。这再一次证明多成分复合体的形成，可用来确保控制途径的特异性。
原始出处:
Received: April 3, 2007; Accepted: July 19, 2007; Published: September 7, 2007
Evidence for Transgenerational Transmission of Epigenetic Tumor Susceptibility in Drosophila
Yalan Xing1, Song Shi1, Long Le2, Crystal A. Lee1, Louise Silver-Morse1, Willis X. Li1*
1 Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, New York, United States of America, 2 Department of Medicine, University of Rochester Medical Center, Rochester, New York, United States of America
Transgenerational epigenetic inheritance results from incomplete erasure of parental epigenetic marks during epigenetic reprogramming at fertilization. The significance of this phenomenon, and the mechanism by which it occurs, remains obscure. Here, we show that genetic mutations in Drosophila may cause epigenetic alterations that, when inherited, influence tumor susceptibility of the offspring. We found that many of the mutations that affected tumorigenesis induced by a hyperactive JAK kinase, HopTum-l, also modified the tumor phenotype epigenetically, such that the modification persisted even in the offspring that did not inherit the modifier mutation. We analyzed mutations of the transcription repressor Krüppel (Kr), which is one of the hopTum-l enhancers known to affect ftz transcription. We demonstrate that the Kr mutation causes increased DNA methylation in the ftz promoter region, and that the aberrant ftz transcription and promoter methylation are both transgenerationally heritable if HopTum-l is present in the oocyte. These results suggest that genetic mutations may alter epigenetic markings in the form of DNA methylation, which are normally erased early in the next generation, and that JAK overactivation disrupts epigenetic reprogramming and allows inheritance of epimutations that influence tumorigenesis in future generations.
Figure 1.Epigenetic Enhancement of hopTum-l Tumorigenicity by Kr1 or TSA Treatment Requires Maternal hopTum-l
(A) Representative F1 progeny adult flies of indicated genotypes with blood tumors (black masses; arrows) in the abdomen are shown. The parents of these flies were hopTum-l/+ females and wild type males (left), or hopTum-l/+ females and Kr1/CyO males (center and right).
(B–D) The tumor indices of progeny flies (genotypes are indicated in bottom right) are shown as mean and standard deviation of at least three independent crosses. “Control cross F1” were from hopTum-l/+ crossed to wild type. Parental genotypes are indicated on the top. FM7 and CyO are marked balancer chromosomes for the X and second chromosomes carrying a wild-type copy of the hop and Kr genes, respectively. Note that when hopTum-l was inherited from the mother (B, D), but not from the father (C), Kr1 epigenetically enhanced hopTum-l tumorigenicity.
(E) Total protein extracts from adult flies raised on food containing 4.5 μM TSA were subjected to SDS-PAGE and blotted with anti-acetyl-H3. The membrane was stripped and reblotted with anti-H3 (full-length gel image is shown in Figure S1). Quantification of three independent blots is shown to the right.
(F) Tumor indices of F1 progeny from wild-type flies treated or untreated (control) with TSA and hopTum-l/+ females or males as shown. The F1 were raised in the absence of TSA. Tumors were counted in F1 that inherited hopTum-l. Note the parent-of-origin differential effects on the tumorigenesis of F1 flies. Three independent crosses with >200 progeny from each cross were counted. *, p < 0.01; **, p < 0.001, Student's t-test.
