WILD-TYPE P53 PROTEIN UNDERGOES CYTOPLASMIC SEQUESTRATION IN UNDIFFERENTIATED NEUROBLASTOMAS BUT NOT IN DIFFERENTIATED TUMORS
WILD-TYPE P53 PROTEIN UNDERGOES CYTOPLASMIC SEQUESTRATION IN UNDIFFERENTIATED NEUROBLASTOMAS BUT NOT IN DIFFERENTIATED TUMORS
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DOI：
10.1073/pnas.92.10.4407
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发表时间：
1995-05-09
影响因子：
11.1
通讯作者：
RIOU, G
中科院分区：
文献类型：
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作者：
MOLL, UM;LAQUAGLIA, M;RIOU, G
神经母细胞瘤（NB）是一种起源于交感神经系统的肿瘤，是儿童期最常见的恶性肿瘤之一。最近几份关于p53基因型的报告发现，在原发性肿瘤中p53基因型实际上是唯一的野生型状态，并且推测p53在NE的发展中不起任何作用。然而，我们在这里报告绝大多数未分化的 NB 表现出野生型 p53 的异常细胞质隔离。 p53 无法转位到细胞核可能阻止了该蛋白质发挥抑制因子的作用。 31 例未分化 NE 中的 30 例 (96%) 显示所有肿瘤细胞的细胞质中野生型 p53 水平升高，同时缺乏核染色。肿瘤组织中的 p53 免疫沉淀显示比正常蛋白水平增加 4.5 至 8 倍。通过全长 cDNA 直接测序和 Southern 印迹分析，所有 10 个肿瘤均含有野生型 p53。此外，在分析的所有 11 个肿瘤中均未发现 MDM-2 基因扩增。相比之下，在 14 例分化型神经节神经母细胞瘤和 1 例良性神经节神经瘤中未检测到 p53 异常。我们得出结论，p53 功能的丧失似乎在未分化 NE 的肿瘤发生中起主要作用。这种肿瘤可能通过抑制 p53 进入细胞核而不是基因突变来消除 p53 的反式激活功能。重要的是，我们的结果表明（i）这可能是 p53 失活的一般机制，不仅限于乳腺癌（我们首先描述它），并且（ii）它发现于以前认为不受 p53 改变影响的肿瘤中。
Neuroblastoma (NB), a tumor arising from the sympathetic nervous system, is one of the most common malignancies in childhood, Several recent reports on the p53 genotype found virtually exclusive wild-type status in primary tumors, and it was postulated that p53 plays no role in the development of NE. Here, however, we report that the vast majority of undifferentiated NBs exhibit abnormal cytoplasmic sequestration of wild-type p53. This inability of p53 to translocate to the nucleus presumably prevents the protein from functioning as a suppressor. Thirty of 31 cases (96%) of undifferentiated NE showed elevated levels of wild-type p53 in the cytoplasm of all tumor cells concomittant with a lack of nuclear staining. p53 immunoprecipitation from tumor tissues showed a 4.5- to 8-fold increase over normal protein levels. All of 10 tumors analyzed harbored wild-type p53 by direct sequencing of full-length cDNA and Southern blot. In addition, no MDM-2 gene amplification was seen in all 11 tumors analyzed. In contrast, no p53 abnormality was detected in 14 differentiated ganglioneuroblastomas and 1 benign ganglioneuroma. We conclude that loss of p53 function seems to play a major role in the tumorigenesis of undifferentiated NE. This tumor might abrogate the transactivating function of p53 by inhibiting its access to the nucleus, rather than by gene mutation. Importantly, our results suggest that (i) this could be a general mechanism for p53 inactivation not limited to breast cancer (where we first described it) and that (ii) it is found in a tumor previously not thought to be affected by p53 alteration.