Takaku K, Oshima M, Miyoshi H, Matsui M, Seldin M F, Taketo M M
Banyu Tsukuba Research Institute (Merck), Japan.
Cell. 1998 Mar 6;92(5):645-56. doi: 10.1016/s0092-8674(00)81132-0.
The DPC4 (SMAD4) gene plays a key role in the TGFbeta signaling pathway. We inactivated its mouse homolog Dpc4 (Smad4). The homozygous mutants were embryonic lethal, whereas the heterozygotes showed no abnormality. We then introduced the Dpc4 mutation into the Apc(delta716) knockout mice, a model for human familial adenomatous polyposis. Because both Apc and Dpc4 are located on chromosome 18, we constructed compound heterozygotes carrying both mutations on the same chromosome by meiotic recombination. In such mice, intestinal polyps developed into more malignant tumors than those in the simple Apc(delta716) heterozygotes, showing an extensive stromal cell proliferation, submucosal invasion, cell type heterogeneity, and in vivo transplantability. These results indicate that mutations in DPC4 (SMAD4) play a significant role in the malignant progression of colorectal tumors.
DPC4（SMAD4）基因在转化生长因子β（TGFβ）信号通路中起关键作用。我们使它的小鼠同源基因Dpc4（Smad4）失活。纯合突变体胚胎致死，而异合子无异常表现。然后我们将Dpc4突变引入Apc（delta716）基因敲除小鼠，该小鼠是人类家族性腺瘤性息肉病的模型。由于Apc和Dpc4都位于18号染色体上，我们通过减数分裂重组构建了在同一条染色体上携带两种突变的复合杂合子。在这类小鼠中，肠道息肉比单纯Apc（delta716）杂合子小鼠发展为更具恶性的肿瘤，表现为广泛的基质细胞增殖、黏膜下浸润、细胞类型异质性以及体内移植性。这些结果表明，DPC4（SMAD4）突变在结直肠癌的恶性进展中起重要作用。
