Inhibitors of Protein Kinase Signaling Pathways Emerging Therapies for Cardiovascular Disease

Protein kinases are enzymes that covalently modify proteins by attaching phosphate groups (from ATP) to serine, threonine, and/or tyrosine residues. In so doing, the functional properties of the protein kinase’s substrates are modified. Protein kinases transduce signals from the cell membrane into the interior of the cell. Such signals include not only those arising from ligand-receptor interactions but also environmental perturbations such as when the membrane undergoes mechanical deformation (ie, cell stretch or shear stress). Ultimately, the activation of signaling pathways that use protein kinases often culminates in the reprogramming of gene expression through the direct regulation of transcription factors or through the regulation of mRNA stability or protein translation. Protein kinases regulate most aspects of normal cellular function. The pathophysiological dysfunction of protein kinase signaling pathways underlies the molecular basis of many cancers and of several manifestations of cardiovascular disease, such as hypertrophy and other types of left ventricular remodeling, ischemia/reperfusion injury, angiogenesis, and atherogenesis. Given their roles in such a wide variety of disease states, protein kinases are rapidly becoming extremely attractive targets for drug discovery, probably second only to heterotrimeric G protein-coupled receptors (eg, angiotensin II). Here, we will review the reasons for this explosion in interest in inhibitors of protein kinases and will describe the process of identifying novel drugs directed against kinases. We will specifically focus on disease states for which drug development has proceeded to the point of clinical or advanced preclinical studies

Live imaging of apoptosis in a novel transgenic mouse highlights its role in neural tube closure

Imaging of caspase activation in living mouse embryos during development suggests that caspase-mediated cell removal facilitates neural tube closure in a temporally regulated manner

Transforming Growth Factor β-Dependent Sequential Activation of Smad, Bim, and Caspase-9 Mediates Physiological Apoptosis in Gastric Epithelial Cells

Transforming growth factor β (TGF-β) has been implicated in the maintenance of homeostasis in various organs, including the gastric epithelium. In particular, TGF-β-induced signaling was shown to be required for the differentiation-associated physiological apoptosis of gastric epithelial cells, but its mechanism has not been well understood. In this study, the molecular mechanism of TGF-β-induced apoptosis was analyzed in a human gastric epithelial cell line, SNU16, as an in vitro model. Expression of Smad7 and Bcl-X(L), but not viral FLIP, was shown to prevent TGF-β-induced apoptosis, indicating an exclusive requirement of the activation of Smad signaling pathway and mitochondrial dysfunction followed by activation of caspase-9. In addition, treatment with TGF-β induced binding of Bim, a proapoptotic Bcl-2 homology domain 3 (BH3)-only protein, to Bcl-X(L), which is dependent on the activation of Smad, and reduction in the expression of Bim by RNA interference decreased the sensitivity to TGF-β-induced apoptosis. Moreover, we found abnormalities in the gastric epithelium of both Bim and caspase-9 knockout mice; these abnormalities were associated with a defect of physiological apoptosis in gastric epithelial cells. These results indicate for the first time that TGF-β is involved in the physiological loss of gastric epithelial cells by activating apoptosis mediated by Smad, Bim, and caspase-9