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首页> 外文期刊>Nature >Promotion of Hras-induced squamous carcinomas by a polymorphic variant of the Patched gene in FVB mice.
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Promotion of Hras-induced squamous carcinomas by a polymorphic variant of the Patched gene in FVB mice.

机译：通过FVB小鼠中Patched基因的多态性变体促进Hras诱导的鳞状癌。

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Mice of the C57BL/6 strain are resistant to the development of skin squamous carcinomas (SCCs) induced by an activated Ras oncogene, whereas FVB/N mice are highly susceptible. The genetic basis of this difference in phenotype is unknown. Here we show that susceptibility to SCC is under the control of a carboxy-terminal polymorphism in the mouse Ptch gene. F1 hybrids between C57BL/6 and FVB/N strains ((B6FVB)F1) are resistant to Ras-induced SCCs, but resistance can be overcome either by elimination of the C57BL/6 Ptch allele (Ptch(B6)) or by overexpression of the FVB/N Ptch allele (Ptch(FVB)) in the epidermis of K5Hras-transgenic (B6FVB)F1 hybrid mice. The human Patched (PTCH) gene is a classical tumour suppressor gene for basal cell carcinomas and medulloblastomas, the loss of which causes increased signalling through the Sonic Hedgehog (SHH) pathway. SCCs that develop in PtchB6+/- mice do not lose the wild-type Ptch gene or show evidence of increased SHH signalling. Although Ptch(FVB) overexpression can promote SCC formation, continued expression is not required for tumour maintenance, suggesting a role at an early stage of tumour cell lineage commitment. The Ptch polymorphism affects Hras-induced apoptosis, and binding to Tid1, the mouse homologue of the Drosophila l(2)tid tumour suppressor gene. We propose that Ptch occupies a critical niche in determining basal or squamous cell lineage, and that both tumour types can arise from the same target cell depending on carcinogen exposure and host genetic background.
机译：C57BL / 6品系的小鼠对激活的Ras癌基因诱导的皮肤鳞状细胞癌（SCC）的产生具有抵抗力，而FVB / N小鼠高度敏感。这种表型差异的遗传基础尚不清楚。在这里，我们显示对SCC的敏感性在小鼠Ptch基因中的羧基末端多态性的控制下。 C57BL / 6和FVB / N菌株（（B6FVB）F1）之间的F1杂种对Ras诱导的SCC具有抗性，但可以通过消除C57BL / 6 Ptch等位基因（Ptch（B6））或通过过度表达C57BL / 6来克服抗性K5Hras转基因（B6FVB）F1杂交小鼠表皮中的FVB / N Ptch等位基因（Ptch（FVB））。人补丁（PTCH）基因是基底细胞癌和成髓细胞瘤的经典肿瘤抑制基因，其丢失会导致通过声波刺猬（SHH）途径增加信号传导。在PtchB6 +/-小鼠中发育的SCC不会丢失野生型Ptch基因，也不会显示出SHH信号增强的证据。尽管Ptch（FVB）的过表达可以促进SCC的形成，但维持肿瘤并不需要持续表达，这提示在肿瘤细胞谱系定型的早期阶段就发挥了作用。 Ptch多态性影响Hras诱导的细胞凋亡，并与果蝇1（2）tid肿瘤抑制基因的小鼠同源物Tid1结合。我们建议Ptch在确定基础或鳞状细胞谱系中占有关键地位，并且这两种类型的肿瘤都可能源于同一靶细胞，具体取决于致癌物暴露和宿主遗传背景。

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