A gradient of RanGTP typically regulates traffic through the nuclear pore by modulating association of receptors with cargo. However, we have demonstrated that the yeast high mobility group box (HMGB) transcription factor Nhp6Ap enters the nucleus via a novel nuclear localization signal (NLS) recognized by calcium calmodulin in a process that does not require Ran. Calmodulin is strictly required for the non-diffusional nuclear entry of Nhp6Ap. Calmodulin and DNA exhibit mutually exclusive binding to NHP6A, indicating that the directionality of Nhp6Ap nuclear accumulation may be driven by DNA-dependent dissociation of calmodulin. Our findings demonstrate that calmodulin can serve as a molecular switch triggering nuclear entry with subsequent dissociation of calmodulin binding upon interaction of cargo with chromatin. This pathway appears to be evolutionarly conserved; mammalian HMGB transcription factors often have two NLSs, one a classical Ran-dependent signal and a second that binds calmodulin. The finding that Nhp6Ap nuclear entry requires calmodulin but not Ran indicates that Nhp6Ap is a good model for studying this poorly understood but evolutionarily conserved calmodlin-dependent nuclear import pathway. This work is described in a paper that has been submitted for publication.

Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2008
Total Cost
$272,868
Indirect Cost
City
State
Country
United States
Zip Code
Bishnupuri, Kumar S; Sainathan, Satheesh K; Bishnupuri, Kislay et al. (2014) Reg4-induced mitogenesis involves Akt-GSK3?-?-Catenin-TCF-4 signaling in human colorectal cancer. Mol Carcinog 53 Suppl 1:E169-80
Sainathan, Satheesh K; Bishnupuri, Kumar S; Aden, Konrad et al. (2012) Toll-like receptor-7 ligand Imiquimod induces type I interferon and antimicrobial peptides to ameliorate dextran sodium sulfate-induced acute colitis. Inflamm Bowel Dis 18:955-67
Bishnupuri, Kumar S; Luo, Qizhi; Sainathan, Satheesh K et al. (2010) Reg IV regulates normal intestinal and colorectal cancer cell susceptibility to radiation-induced apoptosis. Gastroenterology 138:616-26, 626.e1-2
Hanover, John A; Love, Dona C; Prinz, William A (2009) Calmodulin-driven nuclear entry: trigger for sex determination and terminal differentiation. J Biol Chem 284:12593-7
Hanover, John A; Love, Dona C; DeAngelis, Nikki et al. (2007) The High Mobility Group Box Transcription Factor Nhp6Ap enters the nucleus by a calmodulin-dependent, Ran-independent pathway. J Biol Chem 282:33743-51