IDENTIFICATION OF A BONE SPECIFIC FUNCTION FOR P53

描述：本申请的长期目标是研究 p53在成骨细胞分化中的作用 阵 为了实现这一目标，提出了旨在澄清何时 以及p53在这条通路中的作用 p53在肿瘤发生中的作用 骨钙素基因表达和其他骨相关基因的调控 将进行差异化研究。 mdm-2的作用， 将研究p53在骨钙素基因调控中的效应子。 将跟踪p53表达和反式激活活性的变化 在体外骨分化过程中， 其对MDM-2的诱导可导致骨钙素表达。 其他 研究将解决p53非依赖性MDM-2形式是否可以 在没有p53的情况下，在这种调节中起作用。 申请人还将 确定p53是否调节胰岛素样生长因子的活性 骨形成过程中结合蛋白3和骨形态发生蛋白2的表达 分化 在可能的情况下，将使用 来自p53杂合转基因小鼠的成骨细胞。 拟议的研究是 目的是增加我们对以下问题的理解：1）确切的作用机制 p53在骨分化和骨钙素基因调控中的作用 mdm-2作为转录激活因子; 3）以及p53 而MDM-2基因可能介导骨成熟。

DESCRIPTION: The long-term goal of this application is to investigate the role of p53 in osteoblast differentiation, a process central to bone formation. Toward this goal, studies are proposed aimed at clarifying when and how p53 might function in this pathway. The role of p53 in the regulation of osteocalcin gene expression and other genes involved in bone differentiation will be investigated. The role of mdm-2, a downstream effector of p53, in osteocalcin gene regulation will be studied. Alterations in p53 expression and transactivation activity will be followed during in vitro bone differentiation to determine the stage and time at which induction of mdm-2 may result in osteocalcin expression. Other studies will address the question of whether p53-independent mdm-2 forms can function in this regulation, in the absence of p53. The applicant will also determine if p53 modulates the activity of the Insulin Like Growth Factor Binding Protein-3 and Bone Morphogenetic Protein-2 expression, during bone differentiation. Wherever possible the studies will be substantiated using osteoblasts from p53 heterozygous transgenic mice. The proposed studies are aimed at increasing our understanding of: 1) the exact mechanism of action of p53 in bone differentiation and osteocalcin gene regulation: 2) the role of mdm-2 as a transcriptional activator; 3) and the mechanisms by which p53 and mdm-2 genes may mediate bone maturation.