Multiple Functions of Protein Inhibitor of Activated STAT1 in Regulating Endothelial Cell Proliferation and Inflammation.

Protein modifications with small ubiquitin–like modifier (SUMO) have been found to play a key role in regulating the formation of atherosclerosis. SUMO proteins covalently modify certain residues of specific target substrates and change the function of these substrates. It has been well established that the protein inhibitor of activated STAT (PIAS) family of proteins has not only SUMO E3 ligase activity, but also transrepression activity. Lerchenmüller et al have now reported a critical role for PIAS1 in regulating S100A6-mediated endothelial cell proliferation. In particular, they show that S100A6 induces PIAS1 expression and, consequently, increases the entry and progression of cell cycle in endothelial cells via inhibiting STAT1-mediated induction of IFITM1 (interferon-inducible transmembrane protein 1; Figure A). It has been reported that the direct inhibition of Thr55 phosphorylation of p53 induced by IFITM1 stabilizes p53 expression and upregulates p53-p21 expression, leading to cell cycle inhibition. Therefore, Lerchenmüller et al assume that this may be one of the regulatory mechanisms by which IFITM1 can inhibit endothelial cell proliferation. These data suggest that in response to vascular endothelial growth factor-A and subsequent S100A6 induction, PIAS1 plays a crucial role in regulating endothelial proliferation. In this editorial, the role of the PIAS family will be briefly reviewed by focusing on the regulation of endothelial functions, including inflammation, proliferation, and Kruppel like factor 2/endothelial nitric oxide synthase expression.