Gilkes Daniele M, Pan Yu, Coppola Domenico, Yeatman Timothy, Reuther Gary W, Chen Jiandong
H. Lee Moffitt Cancer Center, MRC3057A, 12902 Magnolia Drive, Tampa, FL 33612, USA.
Mol Cell Biol. 2008 Mar;28(6):1999-2010. doi: 10.1128/MCB.01633-07. Epub 2008 Jan 2.
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 1 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 approximately 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.
MDMX是p53转录活性和应激反应的重要调节因子。MDMX的过表达和基因扩增与p53失活及肿瘤发展有关。与MDM2不同，MDMX不能被p53诱导，其在转录水平的调控知之甚少。我们发现肿瘤细胞系中MDMX的水平与启动子活性和mRNA水平密切相关。激活的K-Ras和胰岛素样生长因子1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。MEK的药理学抑制导致肿瘤细胞系中MDMX下调。在大约50%的人类结肠肿瘤中检测到MDMX过表达，并且与细胞外信号调节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调控。这种机制可能保护正常增殖细胞免受p53影响，但在肿瘤发展过程中也会阻碍p53反应。
