Nature: MDMX的遗传放大导致p53在视网膜母细胞瘤中失活
生物谷报道: 过去认为，在多数人类肿瘤中，细胞肿瘤抑制基因Rb和p53都是失活的，而视网膜母细胞瘤（retinoblastoma）是一个例外，在这种肿瘤中，仅仅视网膜母细胞瘤基因Rb1的突变，就足以诱发肿瘤，该肿瘤是源自固有的抗凋亡细胞的突变，因而可以绕过p53信号通路。然而近期美国研究人员的一项发现显示，这种观点可能是基于一个误解，并提出在视网膜母细胞瘤中，同样存在p53通路的失活。该研究结果发表于
这项研究指出，由于人类视网膜母细胞瘤表达野生型p53基因，所以过去人们假设p53通道是完好的，然而在Arf-MDM2/MDMX-p53通道中的其他基因的状态没有被考虑。现在，研究人员在人类视网膜母细胞瘤中识别出了一种遗传放大现象，即在视网膜母细胞瘤形成过程中，MDMX基因扩增，其编码的MDMX蛋白表达量升高。这种遗传放大是p53在Rb1缺失的视网膜细胞中被抑制的机制。
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.
这项研究不仅证明了在视网膜母细胞瘤中存在着Arf-MDM2/MDMX-p53通道的失活，更重要的是，该通路中由放大的基因编码的蛋白（MDMX）可能是化学疗法治疗视网膜母细胞瘤的理想靶点，这为对付这种难以治愈的少儿癌症提供了新的思路。
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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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