Patched2 modulates tumorigenesis in Patched1 heterozygous mice
Patched2 modulates tumorigenesis in Patched1 heterozygous mice
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DOI：
10.1158/0008-5472.can-06-0505
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发表时间：
2006-07-15
期刊：
影响因子：
11.2
通讯作者：
McKinnon, Peter J.
中科院分区：
文献类型：
--
作者：
Lee, Youngsoo;Miller, Heather L.;McKinnon, Peter J.
Sonic Hedgehog（SHH）受体Patched 1（Ptch 1）对胚胎发育至关重要，其丢失与肿瘤发生有关。在小鼠和人类中，一个Ptch 1拷贝的生殖细胞系失活易患基底细胞癌和髓母细胞瘤。在许多情况下，由Ptch 1功能扰动引起的髓母细胞瘤导致高度相似基因Patched 2（Ptch 2）的伴随上调。由于Ptch 2的表达增加与髓母细胞瘤和其他肿瘤相关，我们通过产生Ptch 2缺陷小鼠来研究Ptch 2在肿瘤抑制中的作用。与Ptch 1（-/-）小鼠形成鲜明对比的是，Ptch 2（-/-）动物出生时是活的，没有明显的缺陷，也不容易患癌症。然而，Ptch 2的丢失与Ptch 1单倍不足相结合显著影响肿瘤形成。与Ptch 1（+/-）动物相比，Ptch 1（+/-）Ptch 2（-/-）和Ptch（+/1）Ptch 2（+/-）动物显示出更高的肿瘤发生率和更广泛的肿瘤类型。因此，Ptch 2调节与Ptch 1单倍不足相关的肿瘤发生。
The sonic hedgehog (SHH) receptor Patched 1 (Ptch1) is critical for embryonic development, and its loss is linked to tumorigenesis. Germ line inactivation of one copy of Ptch1 predisposes to basal cell carcinoma and medulloblastoma in mouse and man. In many cases, medulloblastoma arising from perturbations of Ptch1 function leads to a concomitant up-regulation of a highly similar gene, Patched2 (Ptch2). As increased expression of Ptch2 is associated with medulloblastoma and other tumors, we investigated the role of Ptch2 in tumor suppression by generating Ptch2-deficient mice. In striking contrast to Ptch1(-/-) mice, Ptch2(-/-) animals were born alive and showed no obvious defects and were not cancer prone. However, loss of Ptch2 markedly affected tumor formation in combination with Ptch1 haploinsufficiency. Ptch1(+/-)Ptch2(-/-) and Ptch(+/1)Ptch2(+/-) animals showed a higher incidence of tumors and a broader spectrum of tumor types compared with Ptch1(+/-) animals. Therefore, Ptch2 modulates tumorigenesis associated with Ptch1 haploinsufficiency.