Bauer Johannes H, Morris Siti Nur Sarah, Chang Chengyi, Flatt Thomas, Wood Jason G, Helfand Stephen L
Department of Molecular Biology, Brown University Providence, RI 02912, USA.
Aging (Albany NY). 2009 Jan;1(1):38-48. doi: 10.18632/aging.100001.
Calorie Restriction (CR) is a well established method of extending life span in a variety of organisms. In the fruit fly D. melanogaster, CR is mediated at least in part by activation of dSir2. In mammalian systems, one of the critical targets of Sir2 is the tumor suppressor p53. This deacetylation of p53 by Sir2 leads to inhibition of p53's transcriptional activity. We have recently shown that inhibition of Dmp53 activity in the fly brain through the use of dominant-negative (DN) constructs that inhibit DNA-binding can extend life span. This life span extension appears to be related to CR, as CR and DN-Dmp53 donot display additive effects on life span. Here we report that life span extension by DN-Dmp53 expression is highly dynamic and can be achieved even when DN-Dmp53 is expressed later in life. In addition, we demonstrate that life span extension by activation of dSir2 and DN-Dmp53 expression are not additive. Furthermore, we show that dSir2 physically interacts with Dmp53 and can deacetylate Dmp53-derived peptides. Taken together, our data demonstrate that Dmp53 is a down stream target of dSir2 enzymatic activity and mediates some aspects of the life span extending effects of CR.
卡路里限制（CR）是一种在多种生物体中已被充分证实的延长寿命的方法。在果蝇黑腹果蝇中，CR至少部分是由dSir2的激活介导的。在哺乳动物系统中，Sir2的关键靶点之一是肿瘤抑制因子p53。Sir2对p53的这种去乙酰化作用导致p53转录活性的抑制。我们最近发现，通过使用抑制DNA结合的显性负性（DN）构建体来抑制果蝇大脑中的Dmp53活性，可以延长寿命。这种寿命延长似乎与CR有关，因为CR和DN-Dmp53对寿命没有叠加效应。在此我们报告，DN-Dmp53表达导致的寿命延长具有高度动态性，即使DN-Dmp53在生命后期表达也能实现。此外，我们证明激活dSir2和DN-Dmp53表达导致的寿命延长没有叠加效应。再者，我们表明dSir2与Dmp53存在物理相互作用，并且能够使Dmp53衍生的肽去乙酰化。综上所述，我们的数据表明Dmp53是dSir2酶活性的下游靶点，并介导了CR延长寿命效应的某些方面。
