導(dǎo)致癌癥的基因能夠比之前人們認(rèn)為的更強(qiáng)大而狡猾的方式搞破壞,！研究人員已經(jīng)證明,，一種叫做JAK的基因能以一種意想不到的方式向著癌癥前進(jìn)。這種基因與人體的一種常見致癌基因有關(guān),。JAK能夠在更廣泛的水平上破壞生物體的DNA活動,，阻礙胚胎發(fā)育早期的一個關(guān)鍵分子事件。
Rochester大學(xué)醫(yī)學(xué)中心的研究救人員將這些發(fā)現(xiàn)發(fā)表在9月7日的Public Library of Science（PLoS）Genetics上,。
研究人員將果蠅作為研究模型獲得以上發(fā)現(xiàn),，而果蠅具有和人類相同的很多信號途徑。通過對果蠅DNA進(jìn)行操作并分析它們在發(fā)育過程種的體型,，研究組獲得了驚人發(fā)現(xiàn)：一種通常能抑制癌癥的基因上DNA序列的突變所導(dǎo)致的促進(jìn)癌癥發(fā)生的效應(yīng)能夠從親代傳遞給子代,，及時這種突變本事并沒有傳遞給后代。
在某些情況下,，親代中的一方攜帶這種突變就足夠影響到后代,，及時這種突變本身并沒有傳遞給后代。
這項(xiàng)研究再一次證實(shí),，研究人員直到近年來才意識到的一個現(xiàn)實(shí)：盡管DNA編碼一直被認(rèn)為是唯一的一代代傳遞下去的遺傳信息,，但實(shí)際上還存在其他更為精妙的遺傳物質(zhì)——一種能夠在代間傳遞的“分子記憶”。
研究人員通過對一種致癌基因JAK激酶基因進(jìn)行研究,，從而獲得了這一發(fā)現(xiàn),。在人體中，一種與與JAK及其相似的生化系統(tǒng)對人體健康至關(guān)重要,，但是它的信號似乎“亂竄”,。該系統(tǒng)在淋巴瘤或白血病的發(fā)生過程中起到一定的作用。
JAK 激酶
JAK 激酶是酪氨酸激酶,，其主要底物是稱為STAT 的轉(zhuǎn)錄因子,。有超過7 種STAT，每個都由特殊系列的JAK激酶磷酸化,。磷酸化在JAK 與受體在質(zhì)膜上結(jié)合時發(fā)生,。一對JAK激酶與活化的受體作用，兩者對保證途徑的正常功能都很重要,。例如,，應(yīng)答干擾素(Interferon)IFNγ的刺激同時需要JAK1和JAK2。
STAT 磷酸化導(dǎo)致同二聚體(Homodimer)和異二聚體(Heterodimer)的形成,。二聚化的基礎(chǔ)是一個亞基中SH2結(jié)構(gòu)域與另一亞基中磷酸化酪氨酸相互作用,。STAT二聚體進(jìn)入核內(nèi)，在有些情況下與其它蛋白質(zhì)共同作用,。它們結(jié)合到靶基因特異性識別元素上,，從而激活靶基因轉(zhuǎn)錄。
一系列相關(guān)的細(xì)胞因子受體,、JAK 激酶和 STAT轉(zhuǎn)錄因子,，其特異性是如何獲得的呢？許多受體能夠激活同一個JAK,，但激活不同的STAT,，這使問題更尖銳化。特異性的控制在于多成分復(fù)合體的形成,，包括受體,、JAKs和STATs。STAT 直接與受體和JAK作用,，每一STAT 的SH2結(jié)構(gòu)域能識別某個受體上的結(jié)合位點(diǎn),，因此特異性的控制在于STAT,。JAK-STAT途徑的激活是瞬間的，其活性能被一個磷酸酶的作用終止,。例如,，紅細(xì)胞生成素(Erythropoietin，血紅細(xì)胞激素)與其受體結(jié)合激活途徑,。另一個成分的結(jié)合則使該途徑終止,。磷酸化酶SH-PTP1通過其SH2結(jié)構(gòu)域結(jié)合到紅細(xì)胞生成素受體的酪氨酸磷酸化位點(diǎn)，受體上這個位點(diǎn)可能由JAK2磷酸化,。磷酸化酶隨后磷酸化JAK2并終止相應(yīng)的STAT的活性,。這形成了一個簡單的反饋回路：紅細(xì)胞生成素受體激活JAK2，JAK2作用于受體的一個位點(diǎn)上,，這個位點(diǎn)被磷酸化酶識別,，反過來作用于JAK2。這再一次證明多成分復(fù)合體的形成,，可用來確?？刂仆緩降奶禺愋浴?/p>
原始出處:
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.
