TGFbeta signaling is initiated when the type I receptor phosphorylates the MAD-related protein, Smad2, on C-terminal serine residues. This leads to Smad2 association with Smad4, translocation to the nucleus, and regulation of transcriptional responses. Here we demonstrate that Smad7 is an inhibitor of TGFbeta signaling. Smad7 prevents TGFbeta-dependent formation of Smad2/Smad4 complexes and inhibits the nuclear accumulation of Smad2. Smad7 interacts stably with the activated TGFbeta type I receptor, thereby blocking the association, phosphorylation, and activation of Smad2. Furthermore, mutations in Smad7 that interfere with receptor binding disrupt its inhibitory activity. These studies thus define a novel function for MAD-related proteins as intracellular antagonists of the type I kinase domain of TGFbeta family receptors.

Early atherosclerotic lesions develop in a topographical pattern that strongly suggests involvement of hemodynamic forces in their pathogenesis. We hypothesized that certain endothelial genes, which exhibit differential responsiveness to distinct fluid mechanical stimuli, may participate in the atherogenic process by modulating, on a local level within the arterial wall, the effects of systemic risk factors. A differential display strategy using cultured human endothelial cells has identified two genes, manganese superoxide dismutase and cyclooxygenase-2, that exhibit selective and sustained up-regulation by steady laminar shear stress (LSS). Turbulent shear stress, a nonlaminar fluid mechanical stimulus, does not induce these genes. The endothelial form of nitric oxide synthase also demonstrates a similar LSSselective pattern of induction. Thus, three genes with potential atheroprotective (antioxidant, antithrombotic, and antiadhesive) activities manifest a differential response to distinct fluid mechanical stimuli, providing a possible mechanistic link between endothelial gene expression and early events in atherogenesis. The activities of these and other LSSresponsive genes may have important implications for the pathogenesis and prevention of atherosclerosis.Vascular endothelium, the single-cell-thick lining of the cardiovascular system, forms a multifunctional, dynamically mutable interface, that is responsive to a variety of pathophysiologic stimuli. Dysfunction of endothelial cells (EC), induced by systemic biochemical risk factors (e.g., hypercholesterolemia, hyperhomocysteinemia, and diabetes), is thought to play a critical role in the development of atherosclerotic vascular disease and its clinical complications (1-3). The strikingly nonrandom distribution of the earliest lesions of atherosclerosis in both humans and experimental animals has suggested to many that hemodynamic forces might be acting as local "biomechanical risk factors"; however, the exact nature of the biomechanical stimuli involved and their influences on EC pathobiology remain ill-defined (4-6). Arterial bifurcations and curvatures, where disturbed flow patterns (flow separation, flow reversal, low amplitude, and fluctuating wall shear stresses) occur, typically are "lesion-prone areas," whereas geometries associated with uniform laminar flow (oscillatory without flow reversal) and relatively constant (time-averaged) wall shear stresses, such as the straight tubular portions of the aorta and its primary tributaries, tend to be "lesion-protected areas" (7-9). Interestingly, these patterns are retained even in genetically modified animals in which systemic risk factors, such as markedly elevated levels of atherogenic plasma lipoproteins, are present (10). These observations indicate that EC may respond differentially to their local fluid mechanical environment, and thus contribute to the characteristic pattern of atherosclerotic lesion development.Although the molecular mechanisms responsible for atherosclerotic lesion initiati...

Vertebrate Pax proteins share a conserved 128-amino-acid DNA-binding motif, the paired domain. The PAX6 gene, which is mutated in the routine Small eye and human aniridia developmental defects, also encodes a second protein with a 14-amino-acid insertion in the paired domain. This protein, which arises by alternative mRNA splicing, exhibits unique DNA-binding properties. Unlike other paired domains, which bind DNA predominantly by their amino termini, the extended Pax6 paired domain interacts with DNA exclusively through its carboxyl terminus. This property can be simulated by deletion of 30 amino-terminal residues from the Pax6 or Pax2 paired domains. Thus, the insertion acts as a molecular toggle to unmask the DNA-binding potential of the carboxyl terminus. The functional nonequivalence of the two Pax6 proteins is underscored by a T ~ C mutation at position -3 of the alternative splice acceptor site that changes the ratio of the two isoforms and causes a distinct human ocular syndrome.

Vascular endothelium is an important transducer and integrator of both humoral and biomechanical stimuli within the cardiovascular system. Utilizing a differential display approach, we have identified two genes, Smad6 and Smad7,