Transcriptional Regulation by PI 3-kinase/Akt Signaling

描述（由申请人提供）： 程序性细胞死亡或凋亡的调节在正常发育和成体组织的维持中起着关键作用。阻止细胞凋亡的存活因子在正常发育过程中起作用，或者当不适当地应用时，导致诸如癌症或神经变性的病理。 许多细胞外存活信号，如生长因子，刺激细胞表面的受体酪氨酸激酶。然后这些信号传播到细胞内第二信使靶点。PI 3-激酶途径通过其下游效应物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上调节基因表达来控制程序性细胞死亡。这些转录因子可以启动促凋亡或抗凋亡的程序。研究已经开始阐明受这些途径影响的基因，然而PI 3-激酶/Akt/GSK-36信号传导的基因靶点仍然不确定。DNA微阵列将被用来分析该途径在生长因子刺激的细胞中的转录效应。 PI 3-激酶/Akt和GSK-36的抑制剂将鉴定对每个途径特异的那些基因。将使用计算工具评估鉴定为PI 3-激酶/Akt和MEK靶标的基因的常见顺式元件。然后通过染色质免疫沉淀法检测预测的顺式元件。

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.