Pemberton P A, Wong D T, Gibson H L, Kiefer M C, Fitzpatrick P A, Sager R, Barr P J
LXR Biotechnology, Richmond, California 94804, USA.
J Biol Chem. 1995 Jun 30;270(26):15832-7. doi: 10.1074/jbc.270.26.15832.
The role of tumor suppressor proteins in the development of malignancy has made the understanding of their molecular mechanisms of action of great importance. Maspin is a tumor suppressor produced by a number of cell types of epithelial origin. Exogenous recombinant maspin has been shown to block the growth, motility, and invasiveness of breast tumor cell lines in vitro and in vivo. Although belonging to the the serine proteinase inhibitor (serpin) superfamily of proteins, the molecular mechanism of maspin is currently unknown. Here we show that the reactive site loop of maspin exists in an exposed conformation that does not require activation by cofactors. The reactive site loop of maspin, however, does not act as an inhibitor of proteinases such as chymotrypsin, elastase, plasmin, thrombin, and trypsin but rather as a substrate. Maspin is also unable to inhibit tissue and urokinase type plasminogen activators. Stability studies show that maspin cannot undergo the stressed-relaxed transition typical of proteinase-inhibitory serpins, and the protein is capable of spontaneous polymerization induced by changes in pH. It is likely, therefore, that maspin is structurally more closely related to ovalbumin and angiotensinogen, and its tumor suppressor activity is independent of a latent or intrinsic trypsin-like serine proteinase-inhibitory activity.
肿瘤抑制蛋白在恶性肿瘤发生过程中的作用使得了解其分子作用机制变得极为重要。Maspin是一种由多种上皮来源的细胞类型产生的肿瘤抑制因子。外源性重组Maspin已被证明在体外和体内均可阻断乳腺肿瘤细胞系的生长、运动和侵袭。尽管Maspin属于丝氨酸蛋白酶抑制剂（serpin）超家族蛋白，但其分子机制目前尚不清楚。在此我们表明，Maspin的反应位点环以一种无需辅因子激活的暴露构象存在。然而，Maspin的反应位点环并不作为诸如胰凝乳蛋白酶、弹性蛋白酶、纤溶酶、凝血酶和胰蛋白酶等蛋白酶的抑制剂，而是作为一种底物。Maspin也无法抑制组织型和尿激酶型纤溶酶原激活剂。稳定性研究表明，Maspin不能经历蛋白酶抑制性serpin典型的应激 - 松弛转变，并且该蛋白能够由pH变化诱导自发聚合。因此，Maspin在结构上可能与卵清蛋白和血管紧张素原更为密切相关，并且其肿瘤抑制活性独立于潜在的或内在的类胰蛋白酶丝氨酸蛋白酶抑制活性。
