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Transforming growth factor-β (TGFβ) signaling drives aneurysm progression in multiple disorders, including Marfan syndrome (MFS), and therapies that inhibit this signaling cascade are in clinical trials. TGFβ can stimulate multiple intracellular signaling pathways, but it is unclear which of these pathways drives aortic disease and, when inhibited, which(More)
Many nuclear-targeted proteins are transported through the nuclear pore complex (NPC) by the importin-alpha:beta receptor. We now show that Npap60 (also called Nup50), a protein previously believed to be a structural component of the NPC, is a Ran binding protein and a cofactor for importin-alpha:beta-mediated import. Npap60 is a tri-stable switch that(More)
Aortic aneurysm is common, accounting for 1-2% of all deaths in industrialized countries. Early theories of the causes of human aneurysm mostly focused on inherited or acquired defects in components of the extracellular matrix in the aorta. Although several mutations in the genes encoding extracellular matrix proteins have been recognized, more recent(More)
Elevated transforming growth factor (TGF)-β signaling has been implicated in the pathogenesis of syndromic presentations of aortic aneurysm, including Marfan syndrome (MFS) and Loeys-Dietz syndrome (LDS). However, the location and character of many of the causal mutations in LDS intuitively imply diminished TGF-β signaling. Taken together, these data have(More)
Crm1 is a member of the karyopherin family of nucleocytoplasmic transport receptors and mediates the export of proteins from the nucleus by forming a ternary complex with cargo and Ran:GTP. This complex translocates through the nuclear pores and dissociates in the cytosol. The yeast protein Yrb2p participates in this pathway and binds Crm1, but its(More)
export by binding directly to the exportin, Crm1, forming a complex that has a higher affinity for RanGTP and cargo than has Crm1 alone (Englmeier et al., 2001; Lind-say et al., 2001). Crm1:RanBP3:RanGTP:cargo exports Summary from the nucleus to the cytoplasm and is disassembled by RanBP1 and the Ran GTPase activating protein, Ran-Many nuclear-targeted(More)
BACKGROUND Current practice guidelines recommend surgical repair of large thoracic aortic aneurysms to prevent fatal aortic dissection or rupture, but limited natural history data exist to support clinical criteria for timely intervention. METHODS AND RESULTS Of 3247 patients with thoracic aortic aneurysm registered in our institutional Thoracic Aortic(More)
Calcium channel blockers (CCBs) are prescribed to patients with Marfan syndrome for prophylaxis against aortic aneurysm progression, despite limited evidence for their efficacy and safety in the disorder. Unexpectedly, Marfan mice treated with CCBs show accelerated aneurysm expansion, rupture, and premature lethality. This effect is both extracellular(More)
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