Ryu S J, An H J, Oh Y S, Choi H R, Ha M K, Park S C
Department of Biochemistry and Molecular Biology, The Aging and Apoptosis Research Center, Seoul National University College of Medicine, Seoul, Korea.
Cell Death Differ. 2008 Nov;15(11):1673-80. doi: 10.1038/cdd.2008.96. Epub 2008 Jul 4.
Major vault protein (MVP), the main component of vault complex, is overexpressed in many multidrug-resistant cancer cell lines, suggesting a possible role for MVP in cell signaling and survival. In this study, we have found that MVP is markedly increased in senescent human diploid fibroblasts (HDFs) as well as in aged organs. We examined whether MVP expression might be affected by apoptotic stress in an aging-dependent manner. We treated young and senescent HDFs with apoptosis-inducing agents such as H(2)O(2), staurosporine and thapsigargin, and monitored MVP expression. We found that MVP expression is markedly reduced in young HDFs but not in senescent HDFs, in response to apoptotic stresses. Downregulation of MVP increased the sensitivity of senescent HDFs to apoptosis. Also, the level of antiapoptotic B-cell lymphoma protein-2 (Bcl-2) was significantly reduced and the accumulation of c-Jun increased in MVP knocked-down senescent HDFs. Moreover, treatment of MVP knocked-down senescent HDFs with SP600125, a specific c-Jun NH(2)-terminal kinase (JNK) inhibitor, restored the level of Bcl-2 protein. Taken together, these results suggest that MVP is important in the resistance of senescent HDFs to apoptosis by modulation of Bcl-2 expression by JNK pathway.
穹窿主蛋白（MVP）是穹窿复合体的主要成分，在许多多药耐药癌细胞系中过表达，提示MVP在细胞信号传导和存活中可能发挥作用。在本研究中，我们发现MVP在衰老的人二倍体成纤维细胞（HDFs）以及衰老器官中显著增加。我们研究了MVP表达是否可能以衰老依赖的方式受到凋亡应激的影响。我们用凋亡诱导剂如过氧化氢（H₂O₂）、星形孢菌素和毒胡萝卜素处理年轻和衰老的HDFs，并监测MVP表达。我们发现，响应凋亡应激时，年轻HDFs中的MVP表达显著降低，而衰老HDFs中则不然。MVP的下调增加了衰老HDFs对凋亡的敏感性。此外，在敲低MVP的衰老HDFs中，抗凋亡的B细胞淋巴瘤蛋白2（Bcl-2）水平显著降低，c-Jun的积累增加。此外，用特异性c-Jun氨基末端激酶（JNK）抑制剂SP600125处理敲低MVP的衰老HDFs，可恢复Bcl-2蛋白水平。综上所述，这些结果表明MVP通过JNK途径调节Bcl-2表达，在衰老HDFs对凋亡的抗性中起重要作用。
