? ? 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. ? ? ?
| Tullai, John W; Schaffer, Michael E; Mullenbrock, Steven et al. (2004) Identification of transcription factor binding sites upstream of human genes regulated by the phosphatidylinositol 3-kinase and MEK/ERK signaling pathways. J Biol Chem 279:20167-77 |
