Role of Mxi1 in ageing organ systems and the regulation of normal and neoplastic growth
Role of Mxi1 in ageing organ systems and the regulation of normal and neoplastic growth
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DOI：
10.1038/31008
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发表时间：
1998-06-04
期刊：
影响因子：
64.8
通讯作者：
DePinho, RA
中科院分区：
文献类型：
--
作者：
Schreiber-Agus, N;Meng, Y;DePinho, RA
Mxi 1属于Mad（Mxi 1）蛋白家族，其作为Myc癌蛋白的有效拮抗剂发挥作用（1-4）。这种拮抗作用部分涉及它们与Myc竞争蛋白Max和共有DNA结合位点以及募集转录辅阻遏物的能力（4-6）。Mad（Mxi 1）蛋白被认为在细胞生长控制和/或诱导和维持分化状态中是必需的（6-7）。与这些作用一致，mxi 1可能是位于10号染色体长臂24-26区的肿瘤抑制基因。该区域是癌症热点，并且此处的突变可能涉及多种癌症，包括前列腺癌（8-10）。在这里，我们发现缺乏Mxi 1的小鼠表现出进行性的多系统异常。这些小鼠在致癌物治疗后或也缺乏Ink 4a时也显示出对肿瘤发生的易感性增加。这种癌症易感表型可能与几种mxi 1缺陷细胞类型（包括前列腺上皮细胞）增殖能力增强相关。我们的研究结果表明，Mxi 1参与了分化器官系统的稳态，在体内作为肿瘤抑制因子，并以功能相关的方式参与Myc网络。
Mxi1 belongs to the Mad (Mxi1) family of proteins, which function as potent antagonists of Myc oncoproteins(1-4). 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(4-6). Mad(Mxi1) proteins have been suggested to be essential in cellular growth control and/or in the induction and maintenance of the differentiated state(6-7) 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(8-10). 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 functionally relevant manner.