Insulin-like growth factors (IGFs) are critical for normal growth and development in vertebrates. IGFs sustain myoblast cell survival and promote differentiation through the activation of intracellular signal transduction pathways leading to alterations in gene expression. These actions may be regulated by changes in the abundance and activity of DNA-specific transcription factors, in part through the actions of transcriptional co-regulatory proteins. Recently, the transcriptional co-activator p300 has been shown to potentiate the activation of muscle-specific genes regulated by the transcription factor MyoD, and to enhance muscle differentiation. The Rotwein laboratory has found that IGF action stimulates muscle cell viability and differentiation, and in preliminary studies I have found that p300 can function as a muscle cell survival factor. The following specific aims will determine if p300 and IGF signaling pathways regulate muscle cell survival by similar mechanisms: 1.To define the role of the transcriptional co-activator, p300, in growth factor-mediated muscle cellsurvival.2. To characterize the mechanisms of p300-mediated myoblast viability. To accomplish these goals, cultured muscle cells will be infected with inducible recombinant adenoviruses expressing the transcriptional co-activators p300 and P/CAF and their derivatives. Studies will focus on their mechanism and determine if IGF signaling intersects with the function of these co-activators.
| Kuninger, David; Wright, Alistair; Rotwein, Peter (2006) Muscle cell survival mediated by the transcriptional coactivators p300 and PCAF displays different requirements for acetyltransferase activity. Am J Physiol Cell Physiol 291:C699-709 |
| Kuninger, David; Stauffer, Daniel; Eftekhari, Siavash et al. (2004) Gene disruption by regulated short interfering RNA expression, using a two-adenovirus system. Hum Gene Ther 15:1287-92 |
