tp53 mutant zebrafish develop malignant peripheral nerve sheath tumors
tp53 mutant zebrafish develop malignant peripheral nerve sheath tumors
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DOI：
10.1073/pnas.0406252102
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发表时间：
2005-01-11
影响因子：
11.1
通讯作者：
Look, AT
中科院分区：
文献类型：
--
作者：
Berghmans, S;Murphey, RD;Look, AT
TP53是人类癌症中最常见的肿瘤抑制基因突变，近50%的肿瘤表现为功能丧失突变。为了进一步阐明涉及TP53和癌症的遗传途径，我们利用了斑马鱼，这是一种强大的脊椎动物模型系统，适合全基因组正向遗传分析和合成致死筛选。利用靶选择诱变策略鉴定了tp53 dna结合域存在错义突变的斑马鱼系。其中两条系的纯合子突变鱼是可存活的，并且表现出与人类癌症中发现的突变（tp53（N168K）和tp53(M214K)）相似的突变。尽管纯合子tp53（N168K）突变体仅在37℃时对温度敏感并抑制辐射诱导的凋亡，但tp53（M214K）胚胎中的细胞在28℃和37℃时均未发生凋亡。与野生型对照胚胎不同，辐照后的tp53（M214K）胚胎也未能上调p21，也没有在G(1)/S检查点停止。从8.5月龄开始，28%的tp53（M214K）突变鱼发生恶性周围神经鞘肿瘤。除了为研究恶性周围神经鞘肿瘤的分子致病途径提供模型外，这些突变斑马鱼品系还为修饰剂筛选提供了独特的平台，以鉴定影响tp53相关途径的基因突变或小分子，包括细胞凋亡、细胞周期延迟和肿瘤抑制。
TP53 is the most frequently mutated tumor suppressor gene in human cancer, with nearly 50% of all tumors exhibiting a loss-of-function mutation. To further elucidate the genetic pathways involving TP53 and cancer, we have exploited the zebrafish, a powerful vertebrate model system that is amenable to whole-genome forward-genetic analysis and synthetic-lethal screens. Zebrafish lines harboring missense mutations in the tp53 DNA-binding domain were identified by using a target-selected mutagenesis strategy. Homozygous mutant fish from two of these lines were viable and exhibited mutations similar to those found in human cancers (tp53(N168K) and tp53(M214K)). Although homozygous tp53(N168K) mutants were temperature-sensitive and suppressed radiation-induced apoptosis only at 37degreesC, cells in the tP53(M214K) embryos failed to undergo apoptosis in response to gamma radiation at both 28 and 37degreesC. Unlike wild-type control embryos, irradiated tp53(M214K) embryos also failed to up-regulate p21 and did not arrest at the G(1)/S checkpoint. Beginning at 8.5 months of age, 28% of tp53(M214K) mutant fish developed malignant peripheral nerve sheath tumors. In addition to providing a model for studying the molecular pathogenic pathways of malignant peripheral nerve sheath tumors, these mutant zebrafish lines provide a unique platform for modifier screens to identify genetic mutations or small molecules that affect tp53-related pathways, including apoptosis, cell-cycle delay, and tumor suppression.