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首页> 外文期刊>Gut: Journal of the British Society of Gastroenterology >Investigation of the atypical FBXW7 mutation spectrum in human tumours by conditional expression of a heterozygous propellor tip missense allele in the mouse intestines
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Investigation of the atypical FBXW7 mutation spectrum in human tumours by conditional expression of a heterozygous propellor tip missense allele in the mouse intestines

机译：通过小鼠肠中杂合螺旋桨末端错义等位基因的条件表达研究人肿瘤中非典型FBXW7突变谱

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Objective: FBXW7 encodes the substrate recognition component of a ubiquitin ligase that degrades targets such as Notch1, c-Jun, c-Myc and cyclin E. FBXW7 mutations occur in several tumour types, including colorectal cancers. The FBXW7 mutation spectrum in cancers is unusual. Some tumours have biallelic loss of function mutations but most have monoallelic missense mutations involving specific arginine residues at β-propellor tips involved in substrate recognition. Design: FBXW7 functional studies have generally used null systems. In order to analyse the most common mutations in human tumours, we created a Fbxw7fl(R482Q)/+ mouse and conditionally expressed this mutation in the intestines using Vill-Cre. We compared these mice with heterozygous null (Fbxw7+/-) mutants. Results: A few sizeable intestinal adenomas occurred in approximately 30% of R482Q/+ and Fbxw7+/- mice at age 300 days. Breeding the R482Q allele onto Apc mutant backgrounds led to accelerated morbidity and increased polyp numbers and size. Within the small bowel, polyp distribution was shifted proximally. Elevated levels of two particular Fbxw7 substrates, Klf5 and Tgif1, were found in normal intestine and adenomas of R482Q/+, R482Q/R482Q and Fbxw7-/- mice, but not Fbxw7+/- animals. On the Apc mutant background, Fbxw7+/- mutants had a phenotype intermediate between Fbxw7 wild-type and R482Q/+ mice. Conclusions: Heterozygous Fbxw7 propellor tip (R482Q) mutations promote intestinal tumorigenesis on an Apc mutant background. Klf5 and Tgif1 are strong candidates for mediating this effect. Although heterozygous null Fbxw7 mutations also promote tumour growth, these have a weaker effect than R482Q. These findings explain the FBXW7 mutation spectrum found in human cancers, and emphasise the need for animal models faithfully to reflect human disease.
机译：目的：FBXW7编码泛素连接酶的底物识别成分，该酶降解降解诸如Notch1，c-Jun，c-Myc和cyclin E等靶标。FBXW7突变发生在几种肿瘤类型中，包括结直肠癌。癌症中的FBXW7突变谱是不寻常的。一些肿瘤具有双等位基因缺失的功能突变，但是大多数肿瘤具有单等位基因错义突变，其中涉及底物识别的β-推进子末端上的特定精氨酸残基。设计：FBXW7功能研究通常使用空系统。为了分析人类肿瘤中最常见的突变，我们创建了Fbxw7fl（R482Q）/ +小鼠，并使用Vill-Cre在肠道中有条件地表达了此突变。我们将这些小鼠与杂合无效（Fbxw7 +/-）突变体进行了比较。结果：年龄大于300天的R482Q / +和Fbxw7 +/-小鼠中约30％发生了一些大肠腺瘤。将R482Q等位基因育种到Apc突变体背景上会加快发病率并增加息肉数量和大小。在小肠内，息肉分布向近侧转移。在R482Q / +，R482Q / R482Q和Fbxw7-/-小鼠的正常肠和腺瘤中发现了两种特定的Fbxw7底物Klf5和Tgif1的水平升高，但未发现Fbxw7 +/-动物。在Apc突变体背景下，Fbxw7 +/-突变体在Fbxw7野生型和R482Q / +小鼠之间具有表型中间。结论：杂合子Fbxw7推进器末端（R482Q）突变在Apc突变体背景下促进肠道肿瘤发生。 Klf5和Tgif1是中介这种效果的强大候选者。尽管杂合的无效Fbxw7突变也促进了肿瘤的生长，但其作用比R482Q弱。这些发现解释了人类癌症中发现的FBXW7突变谱，并强调了忠实地建立动物模型以反映人类疾病的必要性。

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