Transcriptional Regulation by PI 3-kinase/Akt Signaling

PI 3-激酶/Akt 信号转导的转录调节

• 批准号: 6798157
• 负责人: JOHN W TULLAI
• 金额: $ 4.89万
• 依托单位: BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-01 至 2005-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6798157
• 关键词: apoptosis; binding sites; biological signal transduction; cell line; gene expression; gene induction /repression; genetic regulatory element; genetic transcription; high throughput technology; immunoprecipitation; microarray technology; phosphatidylinositol 3 kinase; postdoctoral investigator; serine threonine protein kinase; transcription factor

DESCRIPTION (provided by applicant): The regulation of programmed cell death, or apoptosis, plays a critical role in both normal development and in the maintenance of adult tissues. Survival factors that prevent apoptosis act in the normal course of development, or, when inappropriately applied, contribute to pathologies such as cancer or neurodegeneration. Many extracellular survival signals, such as growth factors, stimulate receptor tyrosine kinases at the cell surface. These signals then propagate to intracellular second messenger targets. The PI 3-kinase pathway regulates a variety of transcription factors via the phosphorylation of its downstream effectors Akt and GSK-3B. Akt and GSK-313 may contribute to the control of programmed cell death by regulating gene expression at the transcriptional level. These transcription factors can initiate programs that are either pro- or anti-apoptotic. Studies have begun to elucidate the genes affected by these pathways, however the gene targets of PI 3-kinase/Akt/GSK-36 signaling remain undefined. DNA microarrays will be employed to profile the transcriptional effects of this pathway in growth factor stimulated cells. Inhibitors of PI 3-kinase/Akt and GSK-36 will identify those genes specific to each pathway. Genes identified as targets of PI 3-kinase/Akt and MEK will be assessed for common cis-elements using computational tools. Predicted cis-elements will then be tested by chromatin immunoprecipitation.

描述(由申请人提供)： 程序性细胞死亡或细胞凋亡的调节在正常发育和成人组织的维持中都发挥着关键作用。阻止细胞凋亡的生存因子在正常的发育过程中起作用，或者当不适当地应用时，会导致癌症或神经退化等病理现象。许多细胞外生存信号，如生长因子，刺激细胞表面的受体酪氨酸激酶。这些信号然后传播到细胞内的第二信使目标。PI-3-K途径通过其下游效应因子Akt和GSK-3B的磷酸化来调节多种转录因子。AKT和GSK-313可能通过在转录水平调控基因表达而参与控制细胞程序性死亡。这些转录因子可以启动促凋亡或抗凋亡的程序。研究已经开始阐明这些通路影响的基因，但PI 3-K/Akt/GSK-36信号转导的基因靶点仍不明确。DNA微阵列将被用来描述这一途径在生长因子刺激细胞中的转录效应。PI 3-Kinase/Akt和GSK-36的抑制剂将识别每条途径特有的这些基因。被确定为PI 3-激酶/Akt和MEK靶标的基因将使用计算工具评估常见的顺式元件。预测的顺式元件随后将通过染色质免疫沉淀进行测试。