Charitè-Universitätsmedizin Berlin, Campus Benjamin Franklin, Centrum für Herz- und Kreislaufmedizin, Berlin, Germany.
Trends Cardiovasc Med. 2010 Aug;20(6):199-203. doi: 10.1016/j.tcm.2011.08.001.
Alternative pre-mRNA splicing is an essential mechanism regulating protein diversity and functional plasticity of the proteome in response to environmental changes. Several factors are involved in this regulatory mechanism, such as serine/arginine-rich (SR) proteins, the Cdc2-like kinase (Clk) family, the dual-specificity tyrosine phosphorylation regulated kinases, the SR protein kinases (SRPK) 1 and 2, the protein kinase B (PKB,Akt), and the DNA topoisomerase I (DNA topo I). Dynamic changes of the phosphorylation state of SR proteins, mediated by the kinases mentioned previously, play an important role in alternative splicing regulation. Through alternative splicing of the tissue factor (TF) pre-mRNA, two naturally occurring forms of TF, the primary initiator of blood coagulation, are expressed in humans-soluble alternatively spliced (as)TF and membrane-bound "full length" (fl)TF. Both isoforms are known to circulate in blood. flTF, rather than asTF, appears to be the major contributor to the thrombogenicity of vascular wall and blood. asTF has been linked more closely to increased cell survival and angiogenesis. We found the expression of asTF and flTF to be reduced in the myocardium of patients with dilated cardiomyopathy, indicating a role of TF in maintaining myocardial structure. Moreover, we demonstrated proinflammatory cytokines to immediately upregulate the expression of both TF isoforms, which was differentially regulated by SR proteins as well as Clks and DNA topo I. We and others have shown that asTF induces cell proliferation, survival, and angiogenesis via signaling pathways different from flTF-induced effects. These data indicate that both TF isoforms influence diverse processes in cardiovascular (patho)biology and are potential targets for antithrombotic, pro-survival, and proangiogenic therapeutic strategies.
可变剪接是一种重要的机制，可调节蛋白质组的蛋白质多样性和功能可塑性，以响应环境变化。几个因素参与了这种调节机制，如丝氨酸/精氨酸丰富（SR）蛋白、CDC2 样激酶（Clk）家族、双特异性酪氨酸磷酸化调节激酶、SR 蛋白激酶（SRPK）1 和 2、蛋白激酶 B（PKB、Akt）和 DNA 拓扑异构酶 I（DNA topo I）。先前提到的激酶介导的 SR 蛋白磷酸化状态的动态变化在可变剪接调节中发挥重要作用。通过组织因子（TF）前体 mRNA 的可变剪接，两种天然存在的 TF 形式，即血液凝固的主要启动子，在人体中表达-可溶性可变剪接（as）TF 和膜结合“全长”（fl）TF。这两种同工型都已知在血液中循环。flTF 而不是 asTF，似乎是血管壁和血液血栓形成的主要贡献者。asTF 与增加细胞存活和血管生成的关系更为密切。我们发现扩张型心肌病患者心肌中 asTF 和 flTF 的表达减少，表明 TF 在维持心肌结构中的作用。此外，我们证明促炎细胞因子可立即上调两种 TF 同工型的表达，这受 SR 蛋白以及 Clks 和 DNA topo I 的差异调节。我们和其他人已经表明，asTF 通过与 flTF 诱导的作用不同的信号通路诱导细胞增殖、存活和血管生成。这些数据表明，两种 TF 同工型都影响心血管（病理）生物学中的多种过程，是抗血栓形成、促存活和促血管生成治疗策略的潜在靶点。
