The Essential Role Of REGγ In Angiogenesis And Its Molecular Mechanisms

Abstract:The proteasome activator REGy is believed to destruct intact mammalian proteins in a ATP and ubiquitin-independent manner, contributed to cell cycle regulation and tumor development. The biological roles of REGy and the potential mechanism are not fully understood. Here we demonstrate REGγ-/-mice showed poor VEGF-induced cornea/aortic ring angiogenesis and defective oxygen-induced retina angiogenesis. REGy also promoted HUVECs migration in vitro. Meanwhile, the underlying molecular mechanism has been further studied. We found PKA catalytic subunit a(PKAca) up-regulated in REGy-depleted HUVECs, MEFs,bone marrow and spleen. REGγ interacted with PKAca in the presence of forskolin, and decreased PKAca protein stability. REGy knockout elevated Foxol phosphorylation in Ser256and caused its nuclear exclusion by enhanced PKAca activity. By analysis of Foxol downstream genes, we show that REGy loss-of-function inhibited either VCAM-1and E-Selectin gene expression or VEGF-induced gene over-expression. Taken together, REGy regulated VCAM-1and E-Selectin gene expression through phosphorylation of Foxol by PKAca, played an important role in angiogenesis.