Laboratory of Anti-tumor Research, Chiba Cancer Center Research Institute, Chiba 260-8717, Japan.
Biochem Biophys Res Commun. 2011 Mar 4;406(1):79-84. doi: 10.1016/j.bbrc.2011.01.114. Epub 2011 Feb 3.
Recently, we have described that CREB (cAMP-responsive element-binding protein) has the ability to transactivate tumor suppressor p53 gene in response to glucose deprivation. In this study, we have found that CREB forms a complex with p53 and represses p53-mediated transactivation of MDM2 but not of p21(WAF1). Immunoprecipitation analysis revealed that CREB interacts with p53 in response to glucose deprivation. Forced expression of CREB significantly attenuated the up-regulation of the endogenous MDM2 in response to p53. By contrast, the mutant form of CREB lacking DNA-binding domain (CREBΔ) had an undetectable effect on the expression level of the endogenous MDM2. During the glucose deprivation-mediated apoptosis, there existed an inverse relationship between the expression levels of MDM2 and p53/CREB. Additionally, p53/CREB complex was dissociated from MDM2 promoter in response to glucose deprivation. Collectively, our present results suggest that CREB preferentially down-regulates MDM2 and thereby contributing to p53-mediated apoptosis in response to glucose deprivation.
最近，我们描述了 cAMP 反应元件结合蛋白（CREB）在葡萄糖剥夺时具有激活肿瘤抑制基因 p53 的能力。在这项研究中，我们发现 CREB 与 p53 形成复合物，抑制 p53 介导的 MDM2 转录激活，但不抑制 p21（WAF1）。免疫沉淀分析显示，CREB 在葡萄糖剥夺时与 p53 相互作用。强制表达 CREB 可显著减弱 p53 对内源性 MDM2 的上调作用。相比之下，缺乏 DNA 结合域的 CREB 突变体（CREBΔ）对内源性 MDM2 的表达水平没有可检测到的影响。在葡萄糖剥夺介导的细胞凋亡过程中，MDM2 和 p53/CREB 的表达水平之间存在反比关系。此外，在葡萄糖剥夺时，p53/CREB 复合物从 MDM2 启动子解离。总之，我们的研究结果表明，CREB 优先下调 MDM2，从而促进葡萄糖剥夺时 p53 介导的细胞凋亡。
