Qiao W, Li A G, Owens P, Xu X, Wang X-J, Deng C-X
Genetics of Development and Disease Branch, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Oncogene. 2006 Jan 12;25(2):207-17. doi: 10.1038/sj.onc.1209029.
Smad4 is the common mediator for TGFbeta signals, which play important functions in many biological processes. To study the role of Smad4 in skin development and epidermal tumorigenesis, we disrupted this gene in skin using the Cre-loxP approach. We showed that absence of Smad4 blocked hair follicle differentiation and cycling, leading to a progressive hair loss of mutant (MT) mice. MT hair follicles exhibited diminished expression of Lef1, and increased proliferative cells in the outer root sheath. Additionally, the skin of MT mice exhibited increased proliferation of basal keratinocytes and epidermal hyperplasia. Furthermore, we provide evidence that the absence of Smad4 resulted in a block of both TGFbeta and bone morphogenetic protein (BMP) signaling pathways, including p21, a well-known cyclin-dependent kinase inhibitor. Consequently, all MT mice developed spontaneous malignant skin tumors from 3 months to 13 months of age. The majority of tumors are malignant squamous cell carcinomas. A most notable finding is that tumorigenesis is accompanied by inactivation of phosphatase and tensin homolog deleted on chromosome 10 (Pten), activation of AKT, fast proliferation and nuclear accumulation of cyclin D1. These observations revealed the essential functions of Smad4-mediated signals in repressing skin tumor formation through the TGFbeta/BMP pathway, which interacts with the Pten signaling pathway.
Smad4是转化生长因子β（TGFβ）信号的共同介导因子，其在许多生物学过程中发挥重要作用。为了研究Smad4在皮肤发育和表皮肿瘤发生中的作用，我们使用Cre-loxP方法在皮肤中破坏了该基因。我们发现，Smad4的缺失阻断了毛囊分化和循环，导致突变（MT）小鼠逐渐脱发。MT毛囊中Lef1的表达减少，外根鞘中的增殖细胞增加。此外，MT小鼠的皮肤显示基底角质形成细胞增殖增加和表皮增生。此外，我们提供的证据表明，Smad4的缺失导致TGFβ和骨形态发生蛋白（BMP）信号通路均受阻，包括著名的细胞周期蛋白依赖性激酶抑制剂p21。因此，所有MT小鼠在3个月至13个月大时均发生自发性恶性皮肤肿瘤。大多数肿瘤为恶性鳞状细胞癌。一个最显著的发现是，肿瘤发生伴随着10号染色体上缺失的磷酸酶和张力蛋白同源物（Pten）的失活、AKT的激活、细胞周期蛋白D1的快速增殖和核积累。这些观察结果揭示了Smad4介导的信号通过TGFβ/BMP途径在抑制皮肤肿瘤形成中的重要作用，该途径与Pten信号通路相互作用。
