Adenosine Deaminase-Related Growth Factors

这个项目涉及一个新的多肽生长因子家族(腺苷脱氨酶相关生长因子或ADGFs)，它是最近从昆虫细胞的条件培养液中发现的成分，也是几种昆虫幼虫唾液腺的产物。它们与腺苷脱氨酶显示出很强的序列相似性，并被预测为分泌的，但有几个变化导致预测它们可能不是脱氨酶，而是具有不同的催化或非催化功能。一名人类家庭成员与遗传病猫眼综合征有牵连。我们已经通过基因组和基因序列分析鉴定了果蝇该家族的五个成员，并发现其中一个在胚胎中胚层中强烈表达的ADGF-A，在成像盘细胞中促进细胞周期的S期的进展。ADGF-A在整个发育过程中都有表达，文献中的数据表明其主要来源可能是唾液腺。其他家族成员也在大多数发育阶段表达，但比ADGF-A表达更弱。我们将完成这些基因在体内的表达模式的分析，测试它们的表达是否受营养调节，并确定是否有果蝇细胞系在培养条件下产生ADGFs。ADGFs的作用模式将通过培养的视盘细胞进行研究，包括与候选细胞表面受体的结合测试，激活的信号转导途径的鉴定，以及这些和其他生长因子如何控制细胞周期参数的研究。这些蛋白质对腺苷可能的催化活性将进行生化测试，并将启动一项合作研究，以分析ADGF-A的三维结构。该项目将有助于我们对生长调控的基本理解，以及导致人类遗传病的潜在机制。

0091348BryantThis project concerns a novel family of polypeptide growth factors (Adenosine Deaminase-related Growth Factors or ADGFs) recently discovered as a component of conditioned medium from insect cells, and as products of the larval salivary gland in several insects. They show strong sequence similarity to the enzyme Adenosine Deaminase and are predicted to be secreted, but have several alterations leading to the prediction that they may not be deaminases but have a different catalytic or non-catalytic function. A human family member has been implicated in the genetic disease Cat-Eye Syndrome. We have identified five members of the family in Drosophila by genomic and cDNA sequence analysis, and shown that one of them, ADGF-A, which is strongly expressed in the embryonic mesoderm, promotes progression through the S phase of the cell cycle in imaginal disc cells. ADGF-A is expressed throughout development, and data in the literature suggest that the main source may be the salivary gland. Other family members are also expressed at most developmental stages, but more weakly than ADGF-A. We will complete our analysis of the expression patterns of these genes in vivo, test whether their expression is regulated by nutrition, and determine whether any Drosophila cell lines produce ADGFs during medium conditioning. The mode of action of the ADGFs will be investigated using cultured imaginal disc cells, including tests for binding to candidate cell-surface receptors, identification of the signal transduction pathways that are activated, and an investigation of how cell-cycle parameters are controlled by these and other growth factors. The possible catalytic activity of these proteins on adenosine will be tested biochemically, and a collaborative study will be launched to analyze the three-dimensional structure of ADGF-A. The project will contribute to our basic understanding of growth regulation, and to the underlying mechanisms leading to human genetic disease.