Regulation of MDMX expression by mitogenic signaling
Regulation of MDMX expression by mitogenic signaling
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DOI：
10.1128/mcb.01633-07
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发表时间：
2008-03-01
影响因子：
5.3
通讯作者：
Chen, Jiandong
中科院分区：
文献类型：
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作者：
Gilkes, Daniele M.;Pan, Yu;Chen, Jiandong
MDMX是p53转录活性和应激反应的重要调节因子。MDMX过表达和基因扩增与p53失活和肿瘤发展有关。与MDM2不同的是，MDMX不受p53的诱导，对其在转录水平上的调控知之甚少。我们发现肿瘤细胞系中MDMX水平与启动子活性和mRNA水平密切相关。活化的K-Ras和胰岛素样生长因子I通过涉及丝裂原活化蛋白激酶和c-Ets-1转录因子的机制在转录水平诱导MDMX表达。药物抑制MEK可导致肿瘤细胞系中MDMX的下调。在接近50%的人类结肠肿瘤中检测到MDMX过表达，并显示出与细胞外信号调节的激酶磷酸化增加密切相关。因此，MDMX的表达受有丝分裂信号通路的调控。这种机制可以保护正常增殖细胞免受p53的影响，但也会阻碍p53在肿瘤发展过程中的反应。
MDMX is an important regulator of p53 transcriptional activity and stress response. MDMX overexpression and gene amplification are implicated in p53 inactivation and tumor development. Unlike MDM2, MDMX is not inducible by p53, and little is known about its regulation at the transcriptional level. We found that MDMX levels in tumor cell lines closely correlate with promoter activity and mRNA level. Activated K-Ras and insulin-like growth factor I induce MDMX expression at the transcriptional level through mechanisms that involve the mitogen-activated protein kinase and c-Ets-1 transcription factors. Pharmacological inhibition of MEK results in down-regulation of MDMX in tumor cell lines. MDMX overexpression was detected in similar to 50% of human colon tumors and showed strong correlation with increased extracellular signal-regulated kinase phosphorylation. Therefore, MDMX expression is regulated by mitogenic signaling pathways. This mechanism may protect normal proliferating cells from p53 but also hamper p53 response during tumor development.