The NAD-dependent histone deacetylase Sir2 plays important roles in regulating gene silencing in yeast and can extend the life span of several model organisms. The mammalian Sir2 ortholog SirT1 has been implicated in the regulation of key factors involved in growth arrest and apoptosis, including p53, NF-?b and Forkhead. We have found that E2F1 regulates SirT1 expression at the promoter level. Furthermore, SirT1 binds to E2F1 and inhibits E2F1 transcriptional and apoptosis functions, forming an apparent negative feedback loop. Knockdown of SirT1 increases E2F1 transcriptional and apoptosis activities. DNA damage by etoposide causes E2F1-dependent induction of SirT1, and knockdown of SirT1 increases sensitivity to etoposide. These results reveal a mutual regulation between E2F1 and SirT1 that affects cellular sensitivity to DNA damage. We also found that phosphorylation of SirT1 on multiple sites may regulate its deacetylase activity. We hypothesize that SirT1 expression and activity are regulated by oncogenic and Stress signals, contributing to tumor cell survival and treatment resistance. We propose the following experiments to investigate the role of SirT1 in tumor cells, and to evaluate the potential of targeting SirT1 in cancer therapy. (1) Investigate the mutual regulation of E2F1 and SirT1. (2) Determine the effects of SirT1 on tumor formation and treatment response. (3) Investigate the regulation of SirT1 by phosphorylation. (4) Investigate the role of SirT1 in ribosomal stress response. These experiments should lead to a better understanding of the role of SirT1 and may identify novel therapeutic targets for cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA121291-04
Application #
7848846
Study Section
Molecular Oncogenesis Study Section (MONC)
Program Officer
Okano, Paul
Project Start
2007-07-11
Project End
2012-05-31
Budget Start
2010-06-01
Budget End
2011-05-31
Support Year
4
Fiscal Year
2010
Total Cost
$285,570
Indirect Cost
Name
H. Lee Moffitt Cancer Center & Research Institute
Department
Type
DUNS #
139301956
City
Tampa
State
FL
Country
United States
Zip Code
33612
Key, Chia-Chi C; Liu, Mingxia; Kurtz, C Lisa et al. (2017) Hepatocyte ABCA1 Deletion Impairs Liver Insulin Signaling and Lipogenesis. Cell Rep 19:2116-2129
Holbrook, Beth C; D'Agostino Jr, Ralph B; Tyler Aycock, S et al. (2017) Adjuvanting an inactivated influenza vaccine with conjugated R848 improves the level of antibody present at 6months in a nonhuman primate neonate model. Vaccine 35:6137-6142
Wajih, Nadeem; Liu, Xiaohua; Shetty, Pragna et al. (2016) The role of red blood cell S-nitrosation in nitrite bioactivation and its modulation by leucine and glucose. Redox Biol 8:415-21
Wailes, Elizabeth M; Levi-Polyachenko, Nicole H (2016) Multi-walled nanotubes for cellular reprogramming of cancer. Nanomedicine 12:955-963
Holbrook, Beth C; D'Agostino Jr, Ralph B; Parks, Griffith D et al. (2016) Adjuvanting an inactivated influenza vaccine with flagellin improves the function and quantity of the long-term antibody response in a nonhuman primate neonate model. Vaccine 34:4712-4717
Liu, Chen; Wajih, Nadeem; Liu, Xiaohua et al. (2015) Mechanisms of human erythrocytic bioactivation of nitrite. J Biol Chem 290:1281-94
Kim, Jong R; Holbrook, Beth C; Hayward, Sarah L et al. (2015) Inclusion of Flagellin during Vaccination against Influenza Enhances Recall Responses in Nonhuman Primate Neonates. J Virol 89:7291-303
Jennings, Ryan N; Grayson, Jason M; Barton, Erik S (2014) Type I interferon signaling enhances CD8+ T cell effector function and differentiation during murine gammaherpesvirus 68 infection. J Virol 88:14040-9
Barton, Erik S; Rajkarnikar, Sujana; Langston, P Kent et al. (2014) Gammaherpesvirus latency differentially impacts the generation of primary versus secondary memory CD8+ T cells during subsequent infection. J Virol 88:12740-51
Blevins, Lance K; Wren, John T; Holbrook, Beth C et al. (2014) Coinfection with Streptococcus pneumoniae negatively modulates the size and composition of the ongoing influenza-specific CD8? T cell response. J Immunol 193:5076-87

Showing the most recent 10 out of 14 publications