Flowchart: Preparation: IKK
 

 


Text Box: IKK


                                          

Text Box: Ikk1


Text Box: Ikk2


                 

Colorectal cancer                             

Breast cancer

Lung cancer                                                          

Mitosis

 

Text Box: Nemo


Text Box: NFKBText Box: Aurora-A                   

                                  

                                                  

                                                                             

                                            

Text Box: C-FosText Box: Ifn-gamma
                                                                      

                                                       

                                    

                                        

2007/10-31/21

Proc Natl Acad Sci U S A. 2007 Oct 15; [Epub ahead of print]Click here to read Links

A role for I{kappa}B kinase 2 in bipolar spindle assembly.

Irelan JT, Murphy TJ, Dejesus PD, Teo H, Xu D, Gomez-Ferreria MA, Zhou Y, Miraglia LJ, Rines DR, Verma IM, Sharp DJ, Tergaonkar V, Chanda SK.

Genomics Institute of the Novartis Research Foundation, 10675 John J. Hopkins Drive, San Diego, CA 92121;

IkappaB kinase 2 (IKK2 or IKKbeta) is a component of the IKK complex that coordinates the cellular response to a diverse set of extracellular stimuli, including cytokines, microbial infection, and stress. In response to an external stimulus, the complex is activated, resulting in the phosphorylation and subsequent proteasome-mediated degradation of IkappaB proteins. This event triggers the nuclear import of the NF-kappaB transcription factor, which activates the transcription of genes that regulate a variety of fundamental biological processes, including immune response, cell survival, and development. Here, we define an essential role for IKK2 in normal mitotic progression and the maintenance of spindle bipolarity. Chemical and genetic perturbation of IKK2 promotes the formation of multipolar spindles and chromosome missegregation. Depletion of IKK2 results in the deregulation of Aurora A protein stability and coincident hyperactivation of a putative Aurora A substrate, the mitotic motor KIF11. These data support a function for IKK2 as an antagonist of Aurora A signaling during mitosis. Additionally, our results indicate a direct role for IKK2 in the maintenance of genome stability and underscore the potential for oncogenic consequences in targeting this kinase for therapeutic intervention.

PMID: 17939994 [PubMed - as supplied by publisher

Proc Natl Acad Sci U S A. 2005 Aug 30;102(35):12425-30. Epub 2005 Aug 22.Click here to read Click here to readLinks

Enhanced NF-kappaB activation and cellular function in macrophages lacking IkappaB kinase 1 (IKK1).

Li Q, Lu Q, Bottero V, Estepa G, Morrison L, Mercurio F, Verma IM.

The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.

IkappaB kinase (IKK) complex plays a key regulatory role in macrophages for NF-kappaB activation during both innate and adaptive immune responses. Because IKK1-/- mice died at birth, we differentiated functional macrophages from embryonic day 15.5 IKK1 mutant embryonic liver. The embryonic liver-derived macrophage (ELDM) showed enhanced phagocytotic clearance of bacteria, more efficient antigen-presenting capacity, elevated secretion of several key proinflammatory cytokines and chemokines, and known NFkappaB target genes. Increased NFkappaB activity in IKK1 mutant ELDM was the result of prolonged degradation of IkappaBalpha in response to infectious pathogens. The delayed restoration of IkappaBalpha in pathogen-activated IKK1-/- ELDM was a direct consequence of uncontrolled IKK2 kinase activity. We hypothesize that IKK1 plays a checkpoint role in the proper control of IkappaBalpha kinase activity in innate and adaptive immunity.

PMID: 16116086 [PubMed - indexed for MEDLINE

 

Curr Biol. 2005 Jul 26;15(14):1291-5.Click here to read Links

Zebrafish IkappaB kinase 1 negatively regulates NF-kappaB activity.

Correa RG, Matsui T, Tergaonkar V, Rodriguez-Esteban C, Izpisua-Belmonte JC, Verma IM.

The Salk Institute for Biological Studies, La Jolla, CA 92037-1099, USA.

The IkappaB kinase (IKK) activity is critical for processing IkappaB inhibitory proteins and activating the NF-kappaB signaling, which is involved in a series of physiological and developmental steps in vertebrates. The IKK activity resides in two catalytic subunits, IKK1 and IKK2, and two regulatory subunits, NEMO and ELKS. IKK2 is the major cytokine-responsive IkappaB kinase because depletion of IKK1 does not interfere with the IKK activity. In fact, IKK1-/- mice display morphological abnormalities that are independent of its kinase activity and NF-kappaB activation. Hence, using zebrafish (Danio rerio) as a model, we examined the evolutionary role of IKK1 in modulating NF-kappaB. Ikk1-/- zebrafish embryos present head and tail malformations and, surprisingly, show upregulation of NF-kappaB-responsive genes and increased NF-kappaB-dependent apoptosis. Overexpression of ikk1 leads to midline structure defects that resemble NF-kappaB blockage in vivo. Zebrafish Ikk1 forms complexes with NEMO that represses NF-kappaB in vertebrate cells. Indeed, truncation of its NEMO binding domain (NBD) restores NF-kappaB-dependent transcriptional activity and, consequently, the ikk1-overexpressing phenotype. Here, we report that Ikk1 negatively regulates NF-kappaB by sequestering NEMO from active IKK complexes, indicating that IKK1 can function as a repressor of NF-kappaB.

PMID: 16051172 [PubMed - indexed for MEDLINE

 

 

 

 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 


]