A common human skin tumour is caused by activating mutations in beta-catenin.
A common human skin tumour is caused by activating mutations in beta-catenin.
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DOI：
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发表时间：
1999
期刊：
影响因子：
30.8
通讯作者：
E. Chan;U. Gat;J. McNiff;E. Fuchs
中科院分区：
文献类型：
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作者：
E. Chan;U. Gat;J. McNiff;E. Fuchs
WNT信号协调了许多发育程序。响应于这种刺激，细胞质β-连环蛋白（由CTNNB 1编码）被稳定化，使得下游转录激活LEF/TCF家族成员。β-连环蛋白/TCF的靶基因之一编码c-MYC，解释了为什么WNT通路的组成性激活会导致癌症，特别是在结肠中。大多数结肠癌是由编码腺瘤性结肠息肉病（APC）的基因突变引起的，APC是一种泛素介导的β-连环蛋白降解所需的蛋白质，但一小部分结肠癌和一些其他癌症含有β-连环蛋白稳定突变。最近，我们发现表达活化的β-连环蛋白的转基因小鼠易发生类似毛母质瘤的皮肤肿瘤。鉴于这些成年小鼠的皮肤也表现出从头毛囊形态发生的迹象，我们想知道人类毛基质瘤是否可能起源于毛基质细胞，以及它们是否可能具有β-连环蛋白稳定突变。在这里，我们探索这种常见的人类皮肤肿瘤的细胞起源和病因。我们在分裂的肿瘤细胞中发现了核LEF-1，这为毛基质瘤来源于毛基质细胞提供了生化证据。这些肿瘤中至少有75%具有影响氨基末端片段的突变，通常涉及磷酸化依赖性，泛素介导的蛋白质降解。CTNNB 1突变的百分比高于迄今为止检查的所有其他人类肿瘤，并直接暗示β-连环蛋白/LEF失调是人类毛基质细胞肿瘤发生的主要原因。
WNT signalling orchestrates a number of developmental programs. In response to this stimulus, cytoplasmic beta-catenin (encoded by CTNNB1) is stabilized, enabling downstream transcriptional activation by members of the LEF/TCF family. One of the target genes for beta-catenin/TCF encodes c-MYC, explaining why constitutive activation of the WNT pathway can lead to cancer, particularly in the colon. Most colon cancers arise from mutations in the gene encoding adenomatous polyposis coli (APC), a protein required for ubiquitin-mediated degradation of beta-catenin, but a small percentage of colon and some other cancers harbour beta-catenin-stabilizing mutations. Recently, we discovered that transgenic mice expressing an activated beta-catenin are predisposed to developing skin tumours resembling pilomatricomas. Given that the skin of these adult mice also exhibits signs of de novo hair-follicle morphogenesis, we wondered whether human pilomatricomas might originate from hair matrix cells and whether they might possess beta-catenin-stabilizing mutations. Here, we explore the cell origin and aetiology of this common human skin tumour. We found nuclear LEF-1 in the dividing tumour cells, providing biochemical evidence that pilomatricomas are derived from hair matrix cells. At least 75% of these tumours possess mutations affecting the amino-terminal segment, normally involved in phosphorylation-dependent, ubiquitin-mediated degradation of the protein. This percentage of CTNNB1 mutations is greater than in all other human tumours examined thus far, and directly implicates beta-catenin/LEF misregulation as the major cause of hair matrix cell tumorigenesis in humans.