Guan Bin, Pungaliya Pooja, Li Xiang, Uquillas Carlos, Mutton Laura N, Rubin Eric H, Bieberich Charles J
Department of Biological Sciences, University of Maryland, Baltimore County, Baltimore, Maryland 21250, USA.
J Biol Chem. 2008 Feb 22;283(8):4834-40. doi: 10.1074/jbc.M708630200. Epub 2007 Dec 12.
The NKX3.1 gene located at 8p21.2 encodes a homeodomain-containing transcription factor that acts as a haploinsufficient tumor suppressor in prostate cancer. Diminished protein expression of NKX3.1 has been observed in prostate cancer precursors and carcinomas. TOPORS is a ubiquitously expressed E3 ubiquitin ligase that can ubiquitinate tumor suppressor p53. Here we report interaction between NKX3.1 and TOPORS. NKX3.1 can be ubiquitinated by TOPORS in vitro and in vivo, and overexpression of TOPORS leads to NKX3.1 proteasomal degradation in prostate cancer cells. Conversely, small interfering RNA-mediated knockdown of TOPORS leads to an increased steady-state level and prolonged half-life of NKX3.1. These data establish TOPORS as a negative regulator of NKX3.1 and implicate TOPORS in prostate cancer progression.
位于8p21.2的NKX3.1基因编码一种含同源结构域的转录因子，该因子在前列腺癌中作为单倍体不足的肿瘤抑制因子发挥作用。在前列腺癌前体和癌组织中已观察到NKX3.1蛋白表达减少。TOPORS是一种普遍表达的E3泛素连接酶，可使肿瘤抑制因子p53泛素化。在此我们报告NKX3.1与TOPORS之间的相互作用。在体外和体内，NKX3.1均可被TOPORS泛素化，并且TOPORS的过表达导致前列腺癌细胞中NKX3.1经蛋白酶体降解。相反，小干扰RNA介导的TOPORS敲低导致NKX3.1的稳态水平升高和半衰期延长。这些数据确立了TOPORS作为NKX3.1的负调节因子，并表明TOPORS与前列腺癌进展有关。
