REGULATION OF POLYPLOIDY BY CYTIDYLYLTRANSFERASE (CT)

胞苷酰转移酶 (CT) 对多倍体的调控

• 批准号: 6489165
• 负责人: ZHENG CUI
• 金额: $ 23.49万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-01-01 至 2003-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6489165
• 关键词: BCL2 gene /protein; DNA replication; cell cycle; cell fusion; cell line; charge coupled device camera; choline; cytosine nucleotides; flow cytometry; gene duplication; gene expression; genetic regulation; lipid biosynthesis; mutant; neoplasm /cancer genetics; nucleotidyltransferase; phosphatidylcholines; phosphorylation; photography; polyploidy; protein structure function; site directed mutagenesis; synchronous cell division; transfection

CTP:phosphocholine cytidylyltransferase (CT) is the rate-limiting enzyme in the CDP-choline pathway for the de novo synthesis of phosphatidylcholine (PC) in the cytoplasm. However over 95 percent of CT is not required for PC synthesis and is present in the nucleus for unknown reasons. Recent studies show that CT also play an important role in the regulation of DNA ploidy. Deficiency of CT can activate the overexpressed B cell lymphoma gene 2 protein (Bcl-2p) to induce the formation of stable and viable tetraploid cells from diplod cells. Expression of CT can suppress the formation of tetraploid cells induced by Bcl-2p. The long-term goal of this proposal is to understand how CT is involved in the regulation of genome duplication. We will test the hypothesis that CT may have a second role, different from catalyzing CDP-choline formation, to regulate the genome duplication. The first specific aim will determine whether this abnormal genome duplication occurs by which one of the following mechanisms: 1) two rounds of DNA synthesis in one cell cycle; 2) failure of mitosis between two S phases or 3) cell fusion between two parental cells. The second specific aim is to determine whether the noncytalytic properties are important for CT to regulate the Bcl-2p-induced genome duplication by studying the CT deletion mutants lacking these properties. The third specific aim will determine whether the catalytic activity for the synthesis of CDP- choline is important for CT in the regulation of genome duplication by studying the inactive CT mutants with point mutation at the catalytic domain. Being active in both PC synthesis and the regulation of genome duplication suggests that CT may coordinate PC synthesis with cell division. The proposed studies will provide insights into 1) the mechanism of polyploidy in cancer cells; 2) the coordination between ploidy control and PC synthesis; 3) a novel role of Bcl-2 in promoting polyploidy. A better understanding of the mechanism that underlines the genome instability in cancer cells will be helpful for designing more efficient strategies of treating cancer.

CTP：磷酸胆碱细胞质溶解酶（CT）是限速酶 在CDP-胆碱途径中，用于从头综合 细胞质中的磷脂酰胆碱（PC）。 但是超过95％ CT不需要PC合成，并且存在于核中 未知原因。 最近的研究表明，CT也起着重要的作用 在DNA倍动的调节中的作用。 CT的不足会激活 过表达的B细胞淋巴瘤基因2蛋白（BCL-2P）诱导 来自外交类细胞的稳定且可行的四倍体细胞的形成。 CT的表达可以抑制四倍体细胞诱导的形成 由BCL-2P。该提议的长期目标是了解CT 参与了基因组重复的调节。 我们将测试 CT可能具有第二个作用的假设，不同于催化 CDP-胆碱形成，以调节基因组重复。 第一个 具体目标将确定这种异常基因组重复是否 发生以下机制之一发生：1）两轮DNA 在一个细胞周期中的合成； 2）两个S阶段之间有丝分裂的失败 或3）两个亲本细胞之间的细胞融合。 第二个特定目标 是确定非溶质特性对于 CT通过研究CT来调节BCL-2P诱导的基因组重复 缺乏这些特性的删除突变体。 第三个特定目标将 确定合成CDP的催化活性是否 胆碱对于CT在调节基因组复制中很重要 研究在催化的非活性CT突变体中具有点突变 领域。 在PC合成和基因组的调节中都活跃 复制表明CT可以与细胞协调PC合成 分配。 拟议的研究将为1） 癌细胞中多倍体的机理； 2） 倍性控制和PC合成； 3）Bcl-2在促进中的新作用 多倍体。更好地理解强调的机制 癌细胞中的基因组不稳定性将有助于设计更多 有效治疗癌症的策略。

项目成果

Attenuated secretion of very low density lipoproteins from McA-RH7777 cells treated with eicosapentaenoic acid is associated with impaired utilization of triacylglycerol synthesized via phospholipid remodeling.

• DOI: 10.1016/j.bbalip.2006.03.018
• 发表时间: 2006-04
• 期刊: Biochimica et biophysica acta
• 作者: K. Tran;Fengcheng Sun;Zheng Cui;G. Thorne‐Tjomsland;Carly St Germain;Louis R. Lapierre;R. McLeod;J. C. Jamieson;Z. Yao