MXI1, a putative tumor suppressor gene, suppresses growth of human glioblastoma cells.
MXI1, a putative tumor suppressor gene, suppresses growth of human glioblastoma cells.
复制标题
DOI：
--
复制
发表时间：
1997-11
期刊：
影响因子：
11.2
通讯作者：
D. Wechsler;C. Shelly;Christy A. Petroff;C. Dang
中科院分区：
文献类型：
--
作者：
D. Wechsler;C. Shelly;Christy A. Petroff;C. Dang
Mxi 1蛋白在与c-Myc家族成员的调节网络中起作用，其中c-Myc激活转录并刺激细胞增殖，而Mxi 1负调节这些作用。因此，在正常水平的c-Myc存在下，MXI 1基因的失活可以抑制分化并增强增殖，因此MXI 1是潜在的肿瘤抑制基因。我们和其他人先前已经将MXI 1基因定位于染色体10 q的远端部分，该区域在许多星形细胞脑肿瘤中被重排或受等位基因丢失的影响。使用第三个MXI 1内含子中新描述的多态性CA微卫星重复序列，我们发现11例信息丰富的胶质母细胞瘤中有7例表现出MXI 1等位基因丢失。序列分析显示，6个MXI 1编码外显子中的任何一个都没有体细胞突变，与MXI 1等位基因丢失的前列腺肿瘤中的结果相似。为了确定MXI 1是否真的可以作为生长抑制因子发挥作用，我们将类固醇诱导的MXI 1表达载体引入U87 MG细胞系，这是一种缺乏内源性MXI 1表达的胶质母细胞瘤细胞系。MXI 1表达的诱导导致生长速率降低和明显的形态学变化。此外，细胞周期分析表明，MXI 1的诱导导致G2-M期细胞蓄积。因此，这些研究支持MXI 1在正常情况下抑制细胞生长的观点，并表明MXI 1功能丧失可能在人胶质母细胞瘤发展中发挥作用。
The Mxi1 protein functions in a regulatory network with members of the c-Myc family, in which c-Myc activates transcription and stimulates cell proliferation, and Mxi1 negatively regulates these actions. Inactivation of the MXI1 gene could, therefore, inhibit differentiation and enhance proliferation in the presence of normal levels of c-Myc, and thus MXI1 is a potential tumor suppressor gene. We and others have previously mapped the MXI1 gene to the distal portion of chromosome 10q, a region that is rearranged or affected by allelic loss in many astrocytic brain tumors. Using a newly described polymorphic CA microsatellite repeat in the third MXI1 intron, we show that 7 of 11 informative glioblastomas demonstrated MXI1 allelic loss. Sequence analysis revealed no somatic mutations in any of the six MXI1 coding exons, similar to findings in prostate tumors with MXI1 allelic loss. To determine whether MXI1 can indeed function as a suppressor of growth, we have introduced a steroid-inducible MXI1 expression vector into the U87MG cell line, a glioblastoma cell line lacking endogenous MXI1 expression. Induction of MXI1 expression resulted in a decreased growth rate and distinct morphological changes. Furthermore, cell cycle analysis demonstrated that induction of MXI1 results in accumulation of cells in the G2-M phase. Thus, these studies support the notion that MXI1 normally functions to suppress cell growth and suggest that loss of MXI1 function may play a role in human glioblastoma development.