Blood Coagulation and Alternative Pre-mRNA Splicing: An Overview

Abstract

Throughout the 20th century, great advances were made in understanding of how blood coagulation occurs, what physiological and biochemical mechanisms are responsible for its regulation, and what genes and their protein products comprise the essential components of the hemostatic network. Recently, complete sequencing of the human genome revealed that the structural diversity of higher eukaryotes cannot be solely attributed to the number of protein-encoding genes, whereas tools of molecular biology helped establish that pre-mRNAs produced by most protein-encoding genes undergo alternative splicing, a mechanism that enables production of multiple protein isoforms by a single gene. Research in the field of thrombosis and hemostasis revealed that the genes encoding several critical proteins at various junctures of the coagulation cascade produce alternatively spliced protein isoforms with distinct structural and biochemical characteristics, revealing a principally novel dimension in the regulation of blood clotting and, possibly, a few novel therapeutic approaches to treatment of abnormal hemostasis. This review summarizes recently published data pertaining to biosynthesis of the alternatively spliced isoforms of tissue factor (TF, or coagulation factor III), tissue factor pathway inhibitor (TFPI), and coagulation factor XI (FXI), and discusses future directions of this continuously evolving area of biomedical research, with an emphasis on molecular mechanics responsible for regulation of constitutive as well as alternative pre-mRNA splicing.

Role of the Phosphatidylinositol 3-Kinase/Protein Kinase B Pathway in Regulating Alternative Splicing of Tissue Factor mRNA in Human Endothelial Cells

“…36 The binding of SR proteins to these motifs was shown to be essential for the differential TF isoform expression in human monocytic cells. 14 Altogether, the results of the present study point to the PI3K/Akt pathway being, at least in part, involved in the differential TF isoform expression at the mRNA level by regulation of alternative splicing processes, possibly mediated through the phosphorylation state and activity of the SR proteins SRp75, SRp55 and SF2/ASF in TNF-α-induced human ECs. Our results provide new insights into the regulatory network of alternative splicing, especially with respect to the differential TF isoform expression in human ECs.…”

“…It has been suggested that asHTF participates in thrombogenesis in vivo, although it is much less procoagulant than flTF in conventional static assays. 6,12,14 Alternatively asHTF may be linked to increased cell proliferation and angiogenesis. 15 Alternative splicing of pre-messenger RNA (pre-mRNA) is an important eukaryotic mechanism for regulating gene expression, protein diversity and functional variability.…”

“…15 Alternative splicing of pre-messenger RNA (pre-mRNA) is an important eukaryotic mechanism for regulating gene expression, protein diversity and functional variability. 14,16 Serine/arginine-rich (SR) proteins are a family of highly conserved factors crucial for constitutive and alternative splicing of pre-mRNA. [16][17][18] Several SR protein kinases have been reported to phosphorylate SR proteins, thereby regulating the activity of SR proteins in alternative splicing processes.…”

Alternative Splicing for Diseases, Cancers, Drugs, and Databases

“…Additionally, alternative splicing reportedly regulates heart development [12], cardiovascular disease [13], blood coagulation [14], cholesterol homeostasis [15], cellular proliferation, apoptosis, immunity [16], and systemic sclerosis [17]. For example, heart-specific knockout of the serine/arginine- (SR-) rich family of splicing factors, ASF/SF2, produces cardiomyopathy and affects splicing of cardiac troponin T and LIM domain-binding protein [18].…”

“…The alternative splicing of blood coagulation-related genes including tissue factor (coagulation factor III), tissue factor pathway inhibitor (TFPI), and coagulation factor XI has been well reviewed [14]. For cholesterol production and uptake, alternative splicing of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) and LDL receptor (LDLR) can suppress their protein activities [21, 22].…”