Zhang Y, Weiler-Guettler H, Chen J, Wilhelm O, Deng Y, Qiu F, Nakagawa K, Klevesath M, Wilhelm S, Böhrer H, Nakagawa M, Graeff H, Martin E, Stern D M, Rosenberg R D, Ziegler R, Nawroth P P
Department of Medicine and Anesthesiology, University of Heidelberg, 69115 Heidelberg, Germany.
J Clin Invest. 1998 Apr 1;101(7):1301-9. doi: 10.1172/JCI925.
Thrombomodulin (TM), recognized as an essential vessel wall cofactor of the antithrombotic mechanism, is also expressed by a wide range of tumor cells. Tumor cell lines subcloned from four patients with malignant melanoma displayed a negative correlation between TM expression and cell proliferation in vitro and in vivo. Overexpression of wild-type TM decreased cell proliferation in vitro and tumor growth in vivo. TM mutants with altered protein C activation capacity lead to a similar effect. In contrast, transfection of melanoma cells with mutant TM constructs, in which a portion of the cytoplasmic or lectin domain was deleted, abrogated the antiproliferative effect associated with overexpression of wild-type TM. Experiments performed with either peptide agonists/antagonists of the thrombin receptor, with hirudin, or with inhibitors of thrombin-TM interaction did not alter the growth inhibitory effect of TM overexpression. These data suggest that TM exerts an effect on cell proliferation independent of thrombin and the thrombin receptor, possibly related to the binding of novel ligands to determinants in the lectin domain which might trigger signal transduction pathways dependent on the cytoplasmic domain.
血栓调节蛋白（TM）被认为是抗血栓形成机制中一种重要的血管壁辅助因子，也在多种肿瘤细胞中表达。从4例恶性黑色素瘤患者中克隆得到的肿瘤细胞系在体外和体内均显示出TM表达与细胞增殖呈负相关。野生型TM的过表达在体外降低了细胞增殖，在体内抑制了肿瘤生长。蛋白C激活能力改变的TM突变体也产生了类似的效果。相反，用缺失部分胞质结构域或凝集素结构域的突变TM构建体转染黑色素瘤细胞，消除了与野生型TM过表达相关的抗增殖作用。使用凝血酶受体的肽激动剂/拮抗剂、水蛭素或凝血酶-TM相互作用抑制剂进行的实验并未改变TM过表达的生长抑制作用。这些数据表明，TM对细胞增殖的作用独立于凝血酶和凝血酶受体，可能与新型配体与凝集素结构域中决定簇的结合有关，这可能触发依赖于胞质结构域的信号转导途径。
