Nuclear Factor-kappaB (NF-kB) is a dynamic, inducible transcription factor that plays an essential role in a large number of cellular processes including immune and inflammatory responses, cell growth/differentiation, and cell survival. NF-kB activity is regulated primarily through its induced nuclear translocation, however additional signals are also required to enhance the ability of nuclear NF-kB to activate transcription. These signals are thought to target the C-terminal transcriptional activation domain (TAD) of the p65 subunit of NF-kB and likely function to regulate the association of transcriptional coactivator and corepressor proteins with NF-kB. It is well established that several coactivators are required in order for NF-kB to activate transcription. These coactivators include the CREB-binding protein (CBP) and its homolog, p300;the p300/CBP associated factor (P/CAF);and members of the steroid receptor coactivator (p160/SRC) family. The ability of NF-kB to activate transcription is also regulated through the interaction with corepressor proteins including the Class I HDACs (HDAC1, HDAC2, and HDAC3) and the Class III HDAC, SIRT1. These proteins negatively regulate the ability of NF-kB to activate transcription. One of the goals of my lab is to identify new proteins that interact with NF-kB in the nucleus to regulate its ability to activate transcription. To accomplish this, we carried out a cytoplasmic yeast two-hybrid screen using the C-terminal domain of the p65 subunit of NF-kB as the bait. Through this screen we identified two proteins, DEK and SSAT2 that either function as a corepressor (DEK) or as a coactivator (SSAT2). Based on these findings, the goal of the research described in this proposal is to better understand how DEK and SSAT2 function to regulate the ability of NF-kB to activate transcription. To accomplish this, the following aims have been developed:
AIM 1 is focused on analysis of the mechanism of DEKmediated repression of transcription;
in AIM 2 we will assess the biological function of DEK-mediated repression and identify proteins that interact with DEK to modulate its ability to repress transcription;and in AIM 3 we will further characterize the role and mechanism of SSAT2-mediated coactivation of NF-kB activity. Through this work we will gain a much more thorough understanding of how the NF- kB transcriptional activation function is regulated.
| Vogel, Nancy L; Boeke, Marta; Ashburner, Brian P (2006) Spermidine/Spermine N1-Acetyltransferase 2 (SSAT2) functions as a coactivator for NF-kappaB and cooperates with CBP and P/CAF to enhance NF-kappaB-dependent transcription. Biochim Biophys Acta 1759:470-7 |
| Sammons, Morgan; Wan, Shan Shan; Vogel, Nancy L et al. (2006) Negative regulation of the RelA/p65 transactivation function by the product of the DEK proto-oncogene. J Biol Chem 281:26802-12 |
