Maintenance of Glucose Homeostasis through Acetylation of the Metabolic Transcriptional Coactivator PGC-1alpha
Annual rept. 9 Jan 2006-8 Jan 2007
JOHNS HOPKINS UNIV BALTIMORE MD
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The purpose of this proposal is to test the hypothesis that acetylation of PGC-1alpha by the Acetyl Transferase GCN5 associated proteins, Pc3 and WDR18, is a key regulatory modification that controls hepatic glucose production. This investigation has a define scope to specifically test how these proteins control the acetylation status of PGC-1alpha and what is the functional effect in blood glucose levels. The major findings of this Research Technical Report are that we have generated specific siRNAs that specifically knock-down Pc3 and WDR18 and control PGC-1alpha transcriptional function. Moreover, we have generated PGC-1alpha acetylation mutants, surprisingly GCN5 still repress these mutant indicating that other sites are also involved. The significance of these results are that we have identified two proteins, Pc3 and WDR18, that control PGC-1alpha activity and that previous acetylation sites identified in PGC-1alpha are no responsible for GCN5-mediated repression of PGC-1alpha. This leads to further effort to identify the specific sites on PGC-1alpha that are mediating the effects of GCN5 to control hepatic glucose production.
- Genetic Engineering and Molecular Biology
- Medicine and Medical Research
- Stress Physiology