SummaryThe G20210A polymorphism has been shown to alter the efficiency of prothrombin mRNA processing. Here we show that the G20210A mutation also alters prothrombin mRNA stability. Three-fold more prothrombin protein and mRNA were produced in NIH-3T3 cells transfected with the prothrombin cDNAs containing the 20210A variant compared to cells expressing the 20210G variant. mRNA stability assays using chimeric globin transcripts harboring the G or A variant of the 97 nt prothrombin 3’-UTR indicated that the 20210G variant conferred greater instability to the globin reporter transcript than the A variant in transfected HepG2 cells. Both variants of the prothrombin 3’-UTR were shown to provide binding sites for a number of cellular proteins including HuR, an RNA binding protein associated with mRNA stability. Our results indicate that the G20210A is a bifunctional polymorphism, as it not only alters the efficiency of mRNA processing, but also the decay rate of prothrombin mRNA.

The mitogen-activated protein (MAP) kinases are involved in both normal renal physiology and in the pathology of various forms of kidney injury, including renal fibrosis. In vitro studies have shown a role for all three MAP kinase (ERK, p38 and JNK) in the production of the major pro-fibrotic factor, transforming growth factor-beta1 (TGF-beta1) by intrinsic renal cell types. There is also considerable cross-talk between TGF-beta1 and MAP kinase signalling pathways in the synthesis and turnover of extracellular matrix by fibroblast-like cells in the kidney. In addition, MAP kinase signalling contributes to TGF-beta1 induced transition of tubular epithelial cells into myofibroblasts. Administration of specific inhibitors of individual MAP kinases has identified a pathogenic role for both p38 and JNK pathways in animal models of renal fibrosis. There is also evidence to suggest that MAP kinases are activated in human renal fibrosis. Thus, blockade of p38 and JNK pathways may have therapeutic potential for the treatment of chronic renal fibrosis.

Identifying the underlying genetic drivers of the heritability of breast cancer prognosis remains elusive. We adapt a network-based approach to handle underpowered complex datasets to provide new insights into the potential function of germline variants in breast cancer prognosis. This network-based analysis studies~7.3 million variants in 84,457 breast cancer patients in relation to breast cancer survival and confirms the results on 12,381 independent patients. Aggregating the prognostic effects of genetic variants across multiple genes, we identify four gene modules associated with survival in estrogen receptor (ER)negative and one in ER-positive disease. The modules show biological enrichment for cancerrelated processes such as G-alpha signaling, circadian clock, angiogenesis, and Rho-GTPases in apoptosis.

Magnesium-induced placental apoptosis is a potent mechanism of placental degeneration in vitro and may represent an important regulator of placental tissue dynamics in vivo. The ability of antioxidants to prevent magnesium-induced placental apoptosis implicates oxidation-reduction-dependent signaling events in this process. Furthermore, these findings provide a basis for further studies of antioxidants in mitigating the adverse effects of preeclampsia.