In this proposal, we provide evidence that the NAD-dependent deacetylase SIRT1 modulates NF-kappa B transcription in non-small cell lung cancer (NSCLC) cells. Data presented in this proposal demonstrate that SIRT1 deacetylates lysine 310 of RelA/p65 subunit of NF-kappa B to inhibit transcription. We find that SIRT1 and NF-kappa B can repress the PTEN promoter through this novel mode of transcriptional repression. The overall goal of the proposal is to understand the mechanisms by which SIRT1 represses NF-kappa B-dependent transcription and elucidate whether this mode of regulation may account for the silencing of the PTEN gene. This hypothesis will be addressed in 2 specific aims.
Aim1 will establish the mechanisms by which SIRT1 regulates NF-kappa B transcription. Experiments will use pharmacological agents that regulate SIRT1 activity as well as SIRTl-specific siRNA to determine the role of this deacetylase in regulating NF-kappa B transcription.
Aim2 will elucidate whether PTEN tumor suppressor gene is regulated in a SIRT1/NF-kappa B-dependent manner. Experiments will include performing chromatin immunoprecipitation and transient reporter assays to determine if the PTEN gene is a target of SIRT1-mediated repression.
| Yeung, F; Ramsey, C S; Popko-Scibor, A E et al. (2015) Regulation of the mitogen-activated protein kinase kinase (MEK)-1 by NAD(+)-dependent deacetylases. Oncogene 34:798-804 |
| Hoberg, Jamie E; Yeung, Fan; Mayo, Marty W (2004) SMRT derepression by the IkappaB kinase alpha: a prerequisite to NF-kappaB transcription and survival. Mol Cell 16:245-55 |
| Yeung, Fan; Hoberg, Jamie E; Ramsey, Catherine S et al. (2004) Modulation of NF-kappaB-dependent transcription and cell survival by the SIRT1 deacetylase. EMBO J 23:2369-80 |
