來自美國國立衛(wèi)生研究院的兩位研究者已經(jīng)發(fā)現(xiàn)了一個聯(lián)健康胎兒的快速生長以及癌癥中不受控制的細(xì)胞分裂的一個新基因.這項新研究的結(jié)果闡明了正常發(fā)育和常見癌癥的遺傳學(xué)基礎(chǔ).
該項目以小鼠和人類組織為研究對象,相關(guān)結(jié)果發(fā)表在PNAS雜志上.文章的作者是就職于施萊佛國家兒童健康與人類發(fā)展研究所(NICHD)的Julian C. Lui博士和Jeffrey Baron醫(yī)學(xué)博士.
Baron博士說：“我們很早之前已經(jīng)知道,一些能夠促進產(chǎn)前和產(chǎn)后早期胎兒快速生長的基因會在癌細(xì)胞中變得異?；钴S.現(xiàn)在,我們確定了一個分子開關(guān),它可以開啟這些基因中的一部分,這項研究結(jié)果為我們理解正常的身體發(fā)育以及某些類型癌癥的異常生長奠定了基礎(chǔ).”
在出生之前,一組由超過200個促生長基因組成的基因組合是非?；钴S的,它們啟動了胎兒的迅速增長.在出生以后,這些基因的表達會被逐步的關(guān)閉,表現(xiàn)為隨著年齡的生長和逐步接近成年,身體的生長會不斷減緩；而在癌細(xì)胞中,這些基因的表達卻被重新開啟了.
其中一個最主要的促生長基因是胰島素樣生長因子(nsulin Growth Factor 2,IGF2 ),這種基因是產(chǎn)前胎兒正常的身體生長所必需的,但是它在許多類型的癌癥中都會被重新激活,尤其在膀胱癌,、前列腺癌以及一些兒童癌癥中表現(xiàn)地極其活躍.
很多年來,科學(xué)家們都不知道是什么控制了IGF2的開啟或關(guān)閉.現(xiàn)在,通過對一系列技術(shù)的利用以及對許多組織類型的研究,Lui和Baron發(fā)現(xiàn)證據(jù)表明,一個特殊的蛋白質(zhì)——E2F3,激活了正常身體發(fā)育和癌癥中的IGF2基因,特別是在膀胱癌和轉(zhuǎn)移性的前列腺癌中.
更廣泛的看,E2F3的調(diào)控對象不只有IGF2,還有其它許多促生長基因組合中的基因.當(dāng)E2F3的水平很高時,它的調(diào)控對象是異?；钴S的,；當(dāng)E2F3水平下降時,這些基因亦如此.從這點看,E2F3很可能作為一個限制身體生長的主控開關(guān)發(fā)揮關(guān)鍵作用.因此,它成為了研究人員理解正常生長和疾病的復(fù)雜遺傳機制的最感興趣的目標(biāo).（生物谷Bioon.com）
doi: 10.1073/pnas.1219079110
PMC:
PMID:
Evidence that Igf2 down-regulation in postnatal tissues and up-regulation in malignancies is driven by transcription factor E2f3
Julian C. Lui1 and Jeffrey Baron
Insulin-like growth factor 2 (IGF2) is an important fetal growth factor. Its expression is dramatically down-regulated in multiple organs after birth but is frequently up-regulated in cancers. The mechanisms that drive down-regulation of IGF2 in postnatal tissues or the up-regulation in malignancy are unclear. We found evidence that E2F transcription factor 3 (E2F3) drives these changes in expression. E2f3 mRNA expression, protein expression, and binding to the Igf2 promoter all decreased with age postnatally in multiple mouse organs. In late juvenile hepatocytes, restoration of high E2f3 expression restored high Igf2 expression, indicating a causal relationship, but this induction did not occur in fetal hepatocytes, which already have high E2f3 and Igf2 expression. Transient expression of E2f3 in both HEK293 cells and in late juvenile hepatocytes were able to activate reporter constructs containing the mouse Igf2 promoter P2, which includes consensus E2F-binding sites. In humans, microarray data revealed declines in E2F3 and IGF2 expression with age similar to the mouse. In addition, E2F3-overexpressing human prostate and bladder cancers showed increased IGF2 expression, and levels of E2F3 and IGF2 mRNA in these cancers were positively correlated. Taken together, the findings suggest that down-regulation of E2f3 with age helps drive the dramatic decline in Igf2 expression in postnatal organs, and E2F3 overexpression in human cancers induces IGF2 overexpression.
