This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. All cells respond to changes in their environment by altering patterns of gene expression. Gene regulation in eukaryotes begins at the initiation of transcription and continues through export and translation of messenger RNAs. In the yeast Saccharomyces cerevisiae, starvation for amino acids generates a signal that leads to an increase in the level of Gcn4p, a transcriptional activator protein. Gcn4p regulates the expression of over 500 genes, including those involved in amino acid biosynthesis. Thus, yeast cells that cannot obtain amino acids from their environment produce their own. Mechanisms by which Gcn4p activates its target genes have been well studied, but it is not clear how these genes are repressed after starvation conditions are relieved. Gcn4p requires the CCR4-NOT co-activator complex for full target gene expression. However, CCR4-NOT also possesses activities involved in the destruction rather than the creation of mRNAs. The overall goal of this research is to determine the exact post-transcriptional role(s) of CCR4-NOT in Gcn4p target gene expression. The mechanisms by which mammalian cells adapt to amino acid limitation are very similar to those in yeast, and they have been implicated in memory formation in mice and survival of hypoxic conditions by human tumors. Since the CCR4-NOT complex is also conserved, results from the proposed work are applicable to studies in mammalian systems.
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