生物谷報道: 過去認(rèn)為,，在多數(shù)人類腫瘤中,，細(xì)胞腫瘤抑制基因Rb和p53都是失活的，而視網(wǎng)膜母細(xì)胞瘤（retinoblastoma）是一個例外,，在這種腫瘤中,，僅僅視網(wǎng)膜母細(xì)胞瘤基因Rb1的突變，就足以誘發(fā)腫瘤,，該腫瘤是源自固有的抗凋亡細(xì)胞的突變,，因而可以繞過P53信號通路。然而近期美國研究人員的一項發(fā)現(xiàn)顯示,，這種觀點可能是基于一個誤解,，并提出在視網(wǎng)膜母細(xì)胞瘤中，同樣存在p53通路的失活,。該研究結(jié)果發(fā)表于11月2日出版的nature雜志上,。
這項研究指出，由于人類視網(wǎng)膜母細(xì)胞瘤表達(dá)野生型p53基因,，所以過去人們假設(shè)p53通道是完好的,，然而在Arf-MDM2/MDMX-p53通道中的其他基因的狀態(tài)沒有被考慮。現(xiàn)在,，研究人員在人類視網(wǎng)膜母細(xì)胞瘤中識別出了一種遺傳放大現(xiàn)象,，即在視網(wǎng)膜母細(xì)胞瘤形成過程中，MDMX基因擴增,，其編碼的MDMX蛋白表達(dá)量升高,。這種遺傳放大是p53在Rb1缺失的視網(wǎng)膜細(xì)胞中被抑制的機制。
a, b, Real-time RT–PCR analysis of p14ARF and MDMX expression was done on normal human fetal retinae at four stages of development and on seven retinoblastomas. Data from duplicate samples were normalized to GAPDH expression and are plotted as fold changes relative to that of FW10 human retinae (1.0-fold). Error bars represent the s.d. of two experiments. c, Samples analysed in a and b were immunoblotted for MDMX and -actin. d–g, FISH analysis for MDMX was done on 49 primary untreated retinoblastomas; tonsil was used as a normal diploid control. Blue fluorescence is the nuclear counterstain; green fluorescence is the internal chromosomal control; red fluorescence is MDMX. h–k, The same 49 retinoblastomas were immunostained for MDMX, MDM2, p53 and p21. A retinoblastoma sample lacking MDMX was used as a negative control (i). Scale bars, 10 m.
這項研究不僅證明了在視網(wǎng)膜母細(xì)胞瘤中存在著Arf-MDM2/MDMX-p53通道的失活,，更重要的是,，該通路中由放大的基因編碼的蛋白（MDMX）可能是化學(xué)療法治療視網(wǎng)膜母細(xì)胞瘤的理想靶點，這為對付這種難以治愈的少兒癌癥提供了新的思路,。
原文下載：
Abstract
Most human tumours have genetic mutations in their Rb and p53 pathways, but retinoblastoma is thought to be an exception. Studies suggest that retinoblastomas, which initiate with mutations in the gene retinoblastoma 1 (RB1), bypass the p53 pathway because they arise from intrinsically death-resistant cells during retinal development. In contrast to this prevailing theory, here we show that the tumour surveillance pathway mediated by Arf, MDM2, MDMX and p53 is activated after loss of RB1 during retinogenesis. RB1-deficient retinoblasts undergo p53-mediated apoptosis and exit the cell cycle. Subsequently, amplification of the MDMX gene and increased expression of MDMX protein are strongly selected for during tumour progression as a mechanism to suppress the p53 response in RB1-deficient retinal cells. Our data provide evidence that the p53 pathway is inactivated in retinoblastoma and that this cancer does not originate from intrinsically death-resistant cells as previously thought. In addition, they support the idea that MDMX is a specific chemotherapeutic target for treating retinoblastoma.
Inactivation of the p53 pathway in retinoblastoma
Nature.2006 Nov 2;444(7115):61-6.
Nikia A. Laurie etal
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