p53 and MDM2 are involved in the regulation of osteocalcin gene expression.
p53 and MDM2 are involved in the regulation of osteocalcin gene expression.
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DOI：
10.1016/j.yexcr.2012.02.022
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发表时间：
2012-05-01
影响因子：
3.7
通讯作者：
Chandar, Nalini
中科院分区：
文献类型：
--
作者：
Chen, Hankui;Kolman, Kevin;Lanciloti, Natalie;Nerney, Michael;Hays, Emily;Robson, Chet;Chandar, Nalini
骨钙素（Osteocalcin， OC）是一种主要的非胶原骨基质蛋白和成骨细胞标志物，其表达仅限于成熟成骨细胞分化后期。在以前的研究中，我们已经表明骨肉瘤失去p53功能，骨钙素基因表达也相应丧失。野生型p53的引入导致骨钙素基因的重新表达。通过凝胶转移和染色质免疫沉淀试验，我们在大鼠OC启动子区域确定了一个假定的p53结合位点，并观察到当p53积累时OC启动子活性增加。p53诱导基因Mdm2是p53水平的一个众所周知的下游调节因子。我们的研究结果显示，当p53和MDM2短暂过表达时，OC启动子活性协同增加。我们进一步证明p53在MDM2蛋白过表达过程中不会被降解。在促分化（DP）培养基处理ROS17/2.8细胞时，OC表达增加，p53、VDR和MDM2水平同时升高，但在DP培养基和MDM2-p53相互作用的小分子抑制剂Nutlin-3共同处理时OC表达显著降低。我们还观察到，当p53和Mdm2存在时，包括Cbfa-1和p300因子，OC启动子活性显著增加。我们的研究结果提示，在某些生理条件下，肿瘤蛋白MDM2可能与p53协同调控成骨细胞分化过程中的骨钙素基因。
Osteocalcin (OC) is a major noncollagenous bone matrix protein and an osteoblast marker whose expression is limited to mature osteoblasts during the late differentiation stage. In previous studies we have shown osteosarcomas to lose p53 function with a corresponding loss of osteocalcin gene expression. Introduction of wild type p53 resulted in re expression of the osteocalcin gene. Using gel shift and chromatin immunopreciptation assays, we have identified a putative p53 binding site within the rat OC promoter region and observed an increase in OC promoter activity when p53 accumulates using a CAT assay. The p53 inducible gene Mdm2 is a well-known downstream regulator of p53 levels. Our results showed a synergistic increase in the OC promoter activity when both p53 and MDM2 were transiently overexpressed. We further demonstrate that p53 is not degraded during overexpression of MDM2 protein. Increased OC expression was observed with concomitantly increased p53, VDR, and MDM2 levels in ROS17/2.8 cells during treatment with differentiation promoting (DP) media, but was significantly decreased when co-treated with DP media and the small molecule inhibitor of MDM2-p53 interaction, Nutlin-3. We have also observed a dramatic increase of the OC promoter activity in the presence of p53 and Mdm2 with inclusion of Cbfa-1 and p300 factors. Our results suggest that under some physiological conditions the oncoprotein MDM2 may cooperate with p53 to regulate the osteocalcin gene during osteoblastic differentiation.
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