A. Kamiya

Roles of fluid shear stress in physiological regulation of vascular structure and function

The effects of fluid shear stress on the function and structure of the vascular system are outlined, based on the findings obtained in our laboratory or of our colleagues. First, it is pointed out that the adaptive response of the vascular wall to flow changes which we observed in the canine carotid artery shunted with the jugular vein altering the internal diameter to keep the wall shear stress constant, can attain the optimum vascular branching structure as predicted in the minimum work model by Murray. Electronmicroscopic studies of similarly shunted arteries revealing various morphological changes in the endothelial cells have suggested that the shear stress initially affects the endothelium. The in vitro experiments using cultured endothelial cells as well have exhibited that the mitotic activity of the cells significantly increases by applying fluid shear stress. From these findings, it is concluded that the adaptive response of the endothelium to the fluid shear stress is an inherent and key process locally regulating the vascular system to be in the most functional state.

The transmembrane nucleoporin NDC1 is required for targeting of ALADIN to nuclear pore complexes.

NDC1 is a transmembrane nucleoporin that is required for NPC assembly and nucleocytoplasmic transport. We show here that NDC1 directly interacts with the nucleoporin ALADIN, mutations of which are responsible for triple-A syndrome, and that this interaction is required for targeting of ALADIN to nuclear pore complexes (NPCs). Furthermore, we show that NDC1 is required for selective nuclear import. Our findings suggest that NDC1-mediated localization of ALADIN to NPCs is essential for selective nuclear protein import, and that abrogation of the interaction between ALADIN and NDC1 may be important for the development of triple-A syndrome.

Mex-3B induces apoptosis by inhibiting miR-92a access to the Bim-3′UTR

Cells respond to a variety of cellular stresses, including DNA damage, by regulating genes whose expression modulates cell cycle arrest, DNA repair, senescence, and/or apoptosis. MicroRNAs (miRNAs) play essential roles in both normal development and disease pathogenesis by destabilizing mRNAs and inhibiting translation. In turn, miRNA biogenesis, turnover, and activity can be regulated by specific RNA-binding proteins. Here we show that Mex-3B, an hnRNP K homology (KH) domain-containing RNA-binding protein, critically modulates DNA stress-induced apoptosis by posttranscriptionally upregulating the pro-apoptotic BH3 (Bcl-2 homology region 3)-only family member Bim. Furthermore, our data indicate that binding of Mex-3B to the 3′-untranslated region (3′UTR) of Bim interferes with the interaction of an Argonaute (Ago)–miR-92a complex with a miR-92a target site present in the Bim RNA. Our results provide novel insights into the posttranscriptional mechanisms that are critical for cellular stress responses.