Loss of p53 synthesis in zebrafish tumors with ribosomal protein gene mutations
Loss of p53 synthesis in zebrafish tumors with ribosomal protein gene mutations
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DOI：
10.1073/pnas.0805036105
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发表时间：
2008-07-29
影响因子：
11.1
通讯作者：
Lees, Jacqueline A.
中科院分区：
文献类型：
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作者：
MacInnes, Alyson W.;Amsterdam, Adam;Lees, Jacqueline A.
携带17种不同核糖体蛋白（rp）基因杂合突变的斑马鱼容易发生恶性外周神经鞘瘤（MPNST），这是一种在实验室斑马鱼品系中很少见到的肿瘤类型。有趣的是，同样罕见的肿瘤类型出现在斑马鱼中，它们是肿瘤抑制基因p53中功能丧失点突变的纯合子。由于这些原因，并且因为p53在大多数人类癌症中被广泛地知道是突变的，所以我们研究了p53在rp（+/-）MPNST中的状态。使用我们提出的斑马鱼p53的单克隆抗体，我们发现，来自rp（+/-）MPNST的细胞产生p53蛋白的能力显着受损，即使在蛋白酶体抑制剂和γ射线的存在下。虽然p53基因的编码区仍然是野生型的，但该基因被转录，并且在rp（+/-）MPNST细胞中总体蛋白质产生速率似乎正常，p53蛋白不被合成。在我们检查的所有MPNST中观察到这种缺陷，这些MPNST来自我们的17条rp基因突变的斑马鱼品系。迄今为止，恶性肿瘤中p53的研究主要集中在p53基因突变或p53蛋白的异常翻译后调节上。我们的研究结果表明，大量的核糖体蛋白是需要在体内的p53蛋白的生产和破坏这种调节最有可能导致肿瘤的发生。
Zebrafish carrying heterozygous mutations for 17 different ribosomal protein (rp) genes are prone to developing malignant peripheral nerve sheath tumors (MPNSTs), a tumor type that is seldom seen in laboratory strains of zebrafish. Interestingly, the same rare tumor type arises in zebrafish that are homozygous for a loss-of-function point mutation in the tumor suppressor gene p53. For these reasons, and because p53 is widely known to be mutated in the majority of human cancers, we investigated the status of p53 in the rp(+/-) MPNSTs. Using monoclonal antibodies that we raised to zebrafish p53, we found that cells derived from rp(+/-) MPNSTs are significantly impaired in their ability to produce p53 protein even in the presence of a proteasome inhibitor and gamma-irradiation. Although the coding regions of the p53 gene remain wild type, the gene is transcribed, and overall protein production rates appear normal in rp(+/-) MPNST cells, p53 protein does not get synthesized. This defect is observed in all MPNSTs we examined that were derived from our 17 zebrafish lines with rp gene mutations. To date, studies of p53 in malignancies have focused predominantly on either p53 gene mutations or the aberrant posttranslational regulation of the p53 protein. Our results show that the appropriate amount of numerous ribosomal proteins is required for p53 protein production in vivo and that disruption of this regulation most likely contributes to tumorigenesis.