Expression of mitotic spindle checkpoint protein hsMAD1 correlates with cellular proliferation and is activated by a gain-of-function p53 mutant.
Expression of mitotic spindle checkpoint protein hsMAD1 correlates with cellular proliferation and is activated by a gain-of-function p53 mutant.
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发表时间：
2002-05
期刊：
影响因子：
11.2
通讯作者：
Y. Iwanaga;K. Jeang
中科院分区：
文献类型：
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作者：
Y. Iwanaga;K. Jeang
人有丝分裂阻滞缺陷蛋白1（Human mitotic arrest deficiency protein 1，hsMAD 1）是有丝分裂纺锤体组装检查点（MSC）的一个组成部分，其监测染色体分离的保真度并防止细胞非整倍性的出现。由于非整倍体是人类癌症的普遍特征，因此了解MSC基因是如何调节的非常重要。在这里，我们分析了人类基因组序列上游的5'最hsMAD 1编码外显子，并确定了一个1.5 kb的片段与启动子活性。hsMad 1启动子，与管家基因的特征一致，是高度GC丰富的，是缺乏TATA盒。突变分析揭示了一个跨越-73到-31的核心区域，这是hsMad 1转录所必需的。令人惊讶的是，虽然MSC的功能，原型诱导的微管抑制剂，有选择性地在有丝分裂过程中，我们发现hsMad 1启动子主要在G1期表达，并响应不微管抑制剂，但促有丝分裂刺激。在原代细胞和转化细胞中，hsMAD 1的细胞内水平与细胞的增殖状态相关。hsMad 1启动子也优先激活的功能获得性p53突变体。综上所述，我们的研究结果表明，hsMAD 1可能链接p53功能的细胞非整倍性的产生和增强激活hsMad 1的功能获得性p53突变体可能有助于某些癌症的预后不良。
Human mitotic arrest deficiency protein 1, hsMAD1, is a component of the mitotic spindle assembly checkpoint (MSC) that monitors fidelity of chromosomal segregation and guards against emergence of cellular aneuploidy. Because aneuploidy is a pervasive characteristic of human cancers, understanding how MSC genes are regulated is important. Here, we have analyzed human genomic sequences upstream of the 5' most hsMAD1 coding exon and have identified a 1.5-kb fragment with promoter activity. The hsMad1 promoter, consistent with characteristics of housekeeping genes, is highly GC rich and is devoid of a TATA-box. Mutational analyses revealed a core region spanning -73 to -31 as being essential for hsMad1 transcription. Surprisingly, although MSC function, prototypically induced by microtubule inhibitors, is active selectively during mitosis, we found the hsMad1 promoter to be expressed predominantly in G1 and to respond not to microtubule inhibitor but to mitogenic stimulus. In primary, as well as transformed cells, intracellular levels of hsMAD1 correlated with the proliferative status of cells. The hsMad1 promoter was also activated preferentially by a gain-of-function p53 mutant. Taken together, our results suggest that hsMAD1 might link p53 function to the generation of cellular aneuuploidy and that heightened activation of hsMad1 by gain-of-function p53 mutants could contribute to the worse prognosis of certain cancers.