The NF-KappaB inducing IKK signalsome complex is the final receiver and integrator of a host of extracellular stress-like and inflammatory response stimuli. The IKK complex consists of two serinelthreonine kinases (IKKalpha and IKKbeta) and a con-catalytic regulatory/docking protein (NEMO/IKKy). IKK(3 and NEMO/IKKgamma are essential for inducing NF-KB nuclear translocation and DNA binding activity in response to mediators of inflammatory responses like TNFalpha and IL-1, while IKKalpha is largely believed to be dispensible for activating NF-KappaB by these stimuli. Surprisingly, we have recently found that IKKalpha is essential for inducing the transcriptional competence of nuclear NF-KappaB subunits in response to inflammatory cytokines, implying that it plays a critical role in activating NF-KB independent of its DNA binding activity. Consequently, one aim of this proposal will be to elaborate the molecular requirements and mechanisms of action of IKKalpha as a co-global mediator (along with IKKbeta and NEMO/IKKgamma) of stress-like responses culminating in NF-kappaB activation. We have also discovered that the IKK signalsome simultaneously co-ordinates the global induction and repression of cellular gene expression. In a second aim we will elaborate the mechanisms of action of the IKK signalsome as a mediator of NF-KappaB dependent gene repression. We have hypothesized that IKK mediated NF-KappaB activation operates like a co-ordinately controlled on/off switch that alters physiological responses in vivo. Interestingly a subset of the genes, which are repressed in response to extracellular stimulus dependent and IKK mediated NF-KB activation, are also induced targets of the E2F-I. E2F-1 is capable of inducing cell cycle arrest, apoptosis and cell cycle progression depending on its degree of activation and the physiological state of the cell. Experimental conditions in primary and established cells will be established, which lead to interference between NF-KB and E2F on specific genomic targets. The physiological effects of IKK/NF-KappaB mediated repression of cell cycle regulated, E2F target genes will also be evaluated.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM066882-02
Application #
6796887
Study Section
Allergy and Immunology Study Section (ALY)
Program Officer
Somers, Scott D
Project Start
2003-09-01
Project End
2007-08-31
Budget Start
2004-09-01
Budget End
2005-08-31
Support Year
2
Fiscal Year
2004
Total Cost
$320,535
Indirect Cost
Name
State University New York Stony Brook
Department
Biochemistry
Type
Schools of Medicine
DUNS #
804878247
City
Stony Brook
State
NY
Country
United States
Zip Code
11794
Penzo, Marianna; Habiel, David M; Ramadass, Mahalakshmi et al. (2014) Cell migration to CXCL12 requires simultaneous IKK? and IKK?-dependent NF-?B signaling. Biochim Biophys Acta 1843:1796-1804
Samaniego, Sylvia; Marcu, Kenneth B (2013) IKK? in myeloid cells controls the host response to lethal and sublethal Francisella tularensis LVS infection. PLoS One 8:e54124
Olivotto, Eleonora; Otero, Miguel; Astolfi, Annalisa et al. (2013) IKK?/CHUK regulates extracellular matrix remodeling independent of its kinase activity to facilitate articular chondrocyte differentiation. PLoS One 8:e73024
Sfikas, Alexandros; Batsi, Christina; Tselikou, Evangelia et al. (2012) The canonical NF-?B pathway differentially protects normal and human tumor cells from ROS-induced DNA damage. Cell Signal 24:2007-23
Kew, Richard R; Penzo, Marianna; Habiel, David M et al. (2012) The IKK?-dependent NF-?B p52/RelB noncanonical pathway is essential to sustain a CXCL12 autocrine loop in cells migrating in response to HMGB1. J Immunol 188:2380-6
Zheng, Ying; Lilo, Sarit; Brodsky, Igor E et al. (2011) A Yersinia effector with enhanced inhibitory activity on the NF-?B pathway activates the NLRP3/ASC/caspase-1 inflammasome in macrophages. PLoS Pathog 7:e1002026
Goldring, Mary B; Otero, Miguel; Plumb, Darren A et al. (2011) Roles of inflammatory and anabolic cytokines in cartilage metabolism: signals and multiple effectors converge upon MMP-13 regulation in osteoarthritis. Eur Cell Mater 21:202-20
Penzo, Marianna; Molteni, Raffaella; Suda, Tomomi et al. (2010) Inhibitor of NF-kappa B kinases alpha and beta are both essential for high mobility group box 1-mediated chemotaxis [corrected]. J Immunol 184:4497-509
Storci, Gianluca; Sansone, Pasquale; Mari, Sara et al. (2010) TNFalpha up-regulates SLUG via the NF-kappaB/HIF1alpha axis, which imparts breast cancer cells with a stem cell-like phenotype. J Cell Physiol 225:682-91
Marcu, Kenneth B; Otero, Miguel; Olivotto, Eleonora et al. (2010) NF-kappaB signaling: multiple angles to target OA. Curr Drug Targets 11:599-613

Showing the most recent 10 out of 22 publications