Schreiber-Agus N, Meng Y, Hoang T, Hou H, Chen K, Greenberg R, Cordon-Cardo C, Lee H W, DePinho R A
Department of Molecular Genetics, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Nature. 1998 Jun 4;393(6684):483-7. doi: 10.1038/31008.
Mxi1 belongs to the Mad (Mxi1) family of proteins, which function as potent antagonists of Myc oncoproteins. This antagonism relates partly to their ability to compete with Myc for the protein Max and for consensus DNA binding sites and to recruit transcriptional co-repressors. Mad(Mxi1) proteins have been suggested to be essential in cellular growth control and/or in the induction and maintenance of the differentiated state. Consistent with these roles, mxi1 may be the tumour-suppressor gene that resides at region 24-26 of the long arm of chromosome 10. This region is a cancer hotspot, and mutations here may be involved in several cancers, including prostate adenocarcinoma. Here we show that mice lacking Mxi1 exhibit progressive, multisystem abnormalities. These mice also show increased susceptibility to tumorigenesis either following carcinogen treatment or when also deficient in Ink4a. This cancer-prone phenotype may correlate with the enhanced ability of several mxi1-deficient cell types, including prostatic epithelium, to proliferate. Our results show that Mxi1 is involved in the homeostasis of differentiated organ systems, acts as a tumour suppressor in vivo, and engages the Myc network in a functionally relevant manner.
Mxi1属于Mad（Mxi1）蛋白家族，该家族蛋白作为Myc癌蛋白的强效拮抗剂发挥作用。这种拮抗作用部分与其与Myc竞争蛋白Max和共有DNA结合位点以及募集转录共抑制因子的能力有关。Mad（Mxi1）蛋白被认为在细胞生长控制和/或分化状态的诱导与维持中至关重要。与这些作用一致，mxi1可能是位于10号染色体长臂24 - 26区域的肿瘤抑制基因。该区域是癌症热点，此处的突变可能与包括前列腺腺癌在内的多种癌症有关。在此我们表明，缺乏Mxi1的小鼠表现出进行性多系统异常。这些小鼠在接受致癌物处理后或同时缺乏Ink4a时，对肿瘤发生的易感性也增加。这种易患癌症的表型可能与包括前列腺上皮在内的几种mxi1缺陷细胞类型增殖能力增强有关。我们的结果表明，Mxi1参与分化器官系统的稳态，在体内作为肿瘤抑制因子发挥作用，并以功能相关的方式参与Myc网络。
