Vetterkind Susanne, Morgan Kathleen G
Boston Biomedical Research Institute, Watertown, MA, USA.
J Cell Mol Med. 2009 May;13(5):887-95. doi: 10.1111/j.1582-4934.2008.00374.x. Epub 2008 May 24.
Par-4 (prostate apoptosis response 4) is a pro-apoptotic protein and tumour suppressor that was originally identified as a gene product up-regulated during apoptosis in prostate cancer cells. Here, we show, for the first time, that Par-4 is expressed and co-localizes with the actin filament bundles in vascular smooth muscle. Furthermore, we demonstrate that targeting of ZIPK to the actin filaments, as observed upon PGF-2alpha stimulation, is inhibited by the presence of a cell permeant Par-4 decoy peptide. The same decoy peptide also significantly inhibits PGF-2alpha induced contractions of smooth muscle tissue. Moreover, knockdown of Par-4 using antisense morpholino nucleotides results in significantly reduced contractility, and myosin light chain and myosin phosphatase target subunit phosphorylation. These results indicate that Par-4 facilitates contraction by targeting ZIPK to the vicinity of its substrates, myosin light chain and MYPT, which are located on the actin filaments. These results identify Par-4 as a novel regulator of myosin light chain phosphorylation in differentiated, contractile vascular smooth muscle.
Par-4（前列腺凋亡反应蛋白4）是一种促凋亡蛋白和肿瘤抑制因子，最初被鉴定为前列腺癌细胞凋亡过程中上调的基因产物。在此，我们首次表明，Par-4在血管平滑肌中表达并与肌动蛋白丝束共定位。此外，我们证明，如在PGF-2α刺激时所观察到的，ZIPK靶向肌动蛋白丝的过程受到细胞穿透性Par-4诱饵肽的抑制。相同的诱饵肽也显著抑制PGF-2α诱导的平滑肌组织收缩。此外，使用反义吗啉代核苷酸敲低Par-4会导致收缩性显著降低，以及肌球蛋白轻链和肌球蛋白磷酸酶靶向亚基磷酸化水平降低。这些结果表明，Par-4通过将ZIPK靶向位于肌动蛋白丝上的底物肌球蛋白轻链和MYPT附近来促进收缩。这些结果确定Par-4是分化的、收缩性血管平滑肌中肌球蛋白轻链磷酸化的新型调节因子。
