Abstract
The c-Myc protein is up-regulated in many different types of cancer, suggesting that a detailed understanding of Myc function is an important goal. Our previous studies have focused on determining the mechanism by which Myc activates transcription using the target gene cad as an experimental model. Previously, we found that Myc activates cad transcription at a post-RNA polymerase II recruitment step and that the Myc transactivation domain interacts with a number of cdk-cyclin complexes. We now extend these studies to determine the role of these cyclin-cdk complexes in Myc-mediated transactivation. We have found that cyclin T1 binding to Myc localizes to the highly conserved Myc Box I, whereas cdk8 binding localizes to the amino-terminal 41 amino acids of the Myc transactivation domain. We showed that recruitment of cdk8 is sufficient for activation of a synthetic promoter construct. In contrast, the ability of Myc to activate transcription of the cad promoter correlates with binding of cyclin T1. Furthermore, recruitment of cyclin T1 to the cad promoter via a Gal4 fusion protein or through protein-protein interaction with the HIV-1 Tat protein can also activate cad transcription. These results suggest that Myc activates transcription by stimulating elongation and that P-TEFb is a key mediator of this process.
Highlights
It is generally believed that Myc-mediated neoplastic transformation is due at least in part to activation of a set of target genes
Based on our findings that Myc can recruit cyclin-cdk complexes and that the cad promoter is activated at a step subsequent to histone acetylation and RNAP II recruitment, we had hypothesized that Myc functions at the cad promoter to recruit a kinase, which phosphorylates the C-terminal domain (CTD) of RNA polymerase II (RNAP II), and stimulate release of a paused RNAP II [33]
We have determined the minimal region of the Myc transactivation domain (TAD) that binds to cyclin T1 and cdk8
Summary
It is generally believed that Myc-mediated neoplastic transformation is due at least in part to activation of a set of target genes. Based on our findings that Myc can recruit cyclin-cdk complexes and that the cad promoter is activated at a step subsequent to histone acetylation and RNAP II recruitment, we had hypothesized that Myc functions at the cad promoter to recruit a kinase, which phosphorylates the C-terminal domain (CTD) of RNA polymerase II (RNAP II), and stimulate release of a paused RNAP II [33] The goals of this current study are to further investigate this hypothesis by defining the regions of the Myc TAD that bind to various cyclin-cdks and to determine if these regions are important in the activation of the cad promoter
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