IDENTIFICATION OF A BONE SPECIFIC FUNCTION FOR P53

描述：此应用程序的长期目标是调查 P53在成骨细胞分化中的作用，成骨细胞分化是骨的中心过程 队形。为了实现这一目标，建议进行研究，以澄清何时 以及P53在这一途径中的作用。P53蛋白在肿瘤发生、发展中的作用 骨钙素基因表达的调控及与骨相关的其他基因 将对差异化进行调查。下游的MDM-2的作用 将对骨钙素基因调控中的P53效应因子进行研究。 P53的表达和反式激活活性的变化将被跟踪 在体外成骨分化过程中确定分化的阶段和时间 MDM-2的诱导可能导致骨钙素的表达。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，在这一调节中发挥作用。申请者还将 确定P53是否调节胰岛素样生长因子的活性 结合蛋白-3和骨形态发生蛋白-2在骨组织中的表达 差异化。在可能的情况下，这些研究将通过使用 P53杂合转基因小鼠的成骨细胞。建议进行的研究包括 旨在增加我们对以下方面的理解：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作为转录激活剂的作用；3)以及P53 MDM-2基因可能参与骨成熟的调控。

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.