Showing papers by "Michael Karin published in 2008"
TL;DR: It is shown, with the use of mice lacking IKK-β in different cell types, that NF-κB is a critical transcriptional activator of HIF-1α and that basal NF-σB activity is required for Hif-1 α protein accumulation under hypoxia in cultured cells and in the liver and brain of hypoxic animals.
Abstract: The hypoxic response is an ancient stress response triggered by low ambient oxygen (O2) (ref. 1) and controlled by hypoxia-inducible transcription factor-1 (HIF-1), whose alpha subunit is rapidly degraded under normoxia but stabilized when O2-dependent prolyl hydroxylases (PHDs) that target its O2-dependent degradation domain are inhibited. Thus, the amount of HIF-1alpha, which controls genes involved in energy metabolism and angiogenesis, is regulated post-translationally. Another ancient stress response is the innate immune response, regulated by several transcription factors, among which NF-kappaB plays a central role. NF-kappaB activation is controlled by IkappaB kinases (IKK), mainly IKK-beta, needed for phosphorylation-induced degradation of IkappaB inhibitors in response to infection and inflammation. IKK-beta is modestly activated in hypoxic cell cultures when PHDs that attenuate its activation are inhibited. However, defining the relationship between NF-kappaB and HIF-1alpha has proven elusive. Using in vitro systems, it was reported that HIF-1alpha activates NF-kappaB, that NF-kappaB controls HIF-1alpha transcription and that HIF-1alpha activation may be concurrent with inhibition of NF-kappaB. Here we show, with the use of mice lacking IKK-beta in different cell types, that NF-kappaB is a critical transcriptional activator of HIF-1alpha and that basal NF-kappaB activity is required for HIF-1alpha protein accumulation under hypoxia in cultured cells and in the liver and brain of hypoxic animals. IKK-beta deficiency results in defective induction of HIF-1alpha target genes including vascular endothelial growth factor. IKK-beta is also essential for HIF-1alpha accumulation in macrophages experiencing a bacterial infection. Hence, IKK-beta is an important physiological contributor to the hypoxic response, linking it to innate immunity and inflammation.
1,340 citations
TL;DR: The results show that the hypothalamic IKKbeta/NF-kappaB program is a general neural mechanism for energy imbalance underlying obesity and suggest that suppression of IKK beta either broadly across the brain or locally within the mediobasal hypothalamus, or specifically in hypothalamic AGRP neurons significantly protects against obesity and glucose intolerance.
1,198 citations
TL;DR: Sestrin1 and Sestrin2 provide an important link between genotoxic stress, p53 and the mTOR signaling pathway and are demonstrated to activate the AMP-responsive protein kinase (AMPK) and target it to phosphorylate TSC2 and stimulate its GAP activity, thereby inhibiting mTOR.
1,126 citations
TL;DR: The most novel findings suggest a connection between inflammation and diseases, such as insulin resistance associated with diabetes mellitus and cancer, which had not or only weakly been appreciated previously.
686 citations
TL;DR: Recent experimental data supporting the hypothesis that inflammation promotes carcinogenesis, and that NF-kappaB signaling is at the heart of such inflammation, are focused on.
604 citations
TL;DR: It is shown that CD40 or BAFF receptor activation result in TRAF3 degradation in a cIAP1-cIAP2- and TRAF2-dependent way owing to enhanced cI AP1, cIap2 TRAF 3-directed ubiquitin ligase activity.
Abstract: The adaptor and signaling proteins TRAF2, TRAF3, cIAP1 and cIAP2 may inhibit alternative nuclear factor-kappaB (NF-kappaB) signaling in resting cells by targeting NF-kappaB-inducing kinase (NIK) for ubiquitin-dependent degradation, thus preventing processing of the NF-kappaB2 precursor protein p100 to release p52. However, the respective functions of TRAF2 and TRAF3 in NIK degradation and activation of alternative NF-kappaB signaling have remained elusive. We now show that CD40 or BAFF receptor activation result in TRAF3 degradation in a cIAP1-cIAP2- and TRAF2-dependent way owing to enhanced cIAP1, cIAP2 TRAF3-directed ubiquitin ligase activity. Receptor-induced activation of cIAP1 and cIAP2 correlated with their K63-linked ubiquitination by TRAF2. Degradation of TRAF3 prevented association of NIK with the cIAP1-cIAP2-TRAF2 ubiquitin ligase complex, which resulted in NIK stabilization and NF-kappaB2-p100 processing. Constitutive activation of this pathway causes perinatal lethality and lymphoid defects.
582 citations
TL;DR: A portrait of the HECT E3s is provided, through the development of small-molecule inhibitors, as an anticancer therapeutic strategy, to link the substrate specificity of HECT-type E 3s with their contribution to tumorigenesis.
488 citations
TL;DR: Hepatocyte-specific p38 alpha ablation enhanced ROS accumulation and liver damage, which were prevented upon administration of an antioxidant, and IL-1 alpha release by necrotic hepatocytes is therefore an important mediator of liver tumorigenesis.
461 citations
TL;DR: NOD2 plays a key role in the B. anthracis-induced inflammatory response by being a critical mediator of IL-1β secretion, and caspase-1 and NOD2 depend on each other for this role.
Abstract: NOD2, a NOD-like receptor (NLR), is an intracellular sensor of bacterial muramyl dipeptide (MDP) that was suggested to promote secretion of the proinflammatory cytokine IL-1β. Yet, the molecular mechanism by which NOD2 can stimulate IL-1β secretion, and its biological significance were heretofore unknown. We found that NOD2 through its N-terminal caspase recruitment domain directly binds and activates caspase-1 to trigger IL-1β processing and secretion in MDP-stimulated macrophages, whereas the C-terminal leucine-rich repeats of NOD2 prevent caspase-1 activation in nonstimulated cells. MDP challenge induces the association of NOD2 with another NLR protein, NALP1, and gel filtration analysis revealed the formation of a complex consisting of NOD2, NALP1, and caspase-1. Importantly, Bacillus anthracis infection induces IL-1β secretion in a manner that depended on caspase-1 and NOD2. In vitro, Anthrax lethal toxin strongly potentiated IL-1β secretion, and that response was NOD2 and caspase-1-dependent. Thus, NOD2 plays a key role in the B. anthracis-induced inflammatory response by being a critical mediator of IL-1β secretion.
379 citations
TL;DR: The importance of autocrine interleukin 6 (IL-6) in lung and breast cancers and implicate IL-6 as an important activator of oncogenic STAT3 in lung adenocarcinomas and of Jagged-1/Notch signaling in breast tumor mammospheres are outlined.
349 citations
TL;DR: The NF-κB signaling pathway has particular relevance to several liver diseases including hepatitis, viral hepatitis induced by HBV and HCV, liver fibrosis and cirrhosis and hepatocellular carcinoma, and is a potential target for development of hepatoprotective agents.
Abstract: The NF-kappaB signaling pathway has particular relevance to several liver diseases including hepatitis (liver infection by Helicobacter, viral hepatitis induced by HBV and HCV), liver fibrosis and cirrhosis and hepatocellular carcinoma. Furthermore, the NF-kappaB signaling pathway is a potential target for development of hepatoprotective agents. Several types of drugs including: selective estrogen receptor modulators (SERMs), antioxidants, proteasome inhibitors, IKK inhibitors and nucleic acid-based decoys have been shown to interfere with NF-kappaB activity at different levels and may be useful for the treatment of liver diseases. However, NF-kappaB also plays an important hepatoprotective function that needs to be taken into consideration during development of new therapeutic regimens.
TL;DR: In this paper, the authors proposed that NF-kappaB transcription factors regulated via the IkappaB kinase (IKK) complex play a critical role in coupling inflammation and cancer and set out to test this hypothesis in mouse models of cancer.
Abstract: A potential link between inflammation and cancer has been suspected for over a century, but the exact molecular mechanisms connecting the two remained nebulous. We proposed that NF-kappaB transcription factors regulated via the IkappaB kinase (IKK) complex play a critical role in coupling inflammation and cancer and have set out to test this hypothesis in mouse models of cancer. Using mice bearing mutations in the genes coding for the IKKbeta and IKKalpha catalytic subunits we obtained evidence supporting a critical role for IKKbeta in tumor promotion and more recently identified the involvement of IKKalpha in metastatogenesis. Whereas the major pro-tumorigenic function of IKKbeta is mediated via NF-kappaB, the pro-metastatic function of IKKalpha is NF-kappaB-independent. In addition to illustrating the critical roles of the two IKK molecules in linking inflammation and cancer and providing an explanation for increased cancer risk in response to persistent infections and inflammation, these results also identify new targets for development of novel anti-cancer therapies and preventive strategies. Instead of targeting the cancer cell itself, as done by conventional anti-cancer drugs, the new therapeutics will target processes that occur within inflammatory cells that are essential for cancer development and progression. Unlike cancer cells, inflammatory cells retain a normal and stable genome and therefore are unlikely to become genetically resistant to therapeutic intervention.
TL;DR: TRAF2, Ubc13, and IKKγ were required for complex assembly and activation of MEKK1 and MAPK cascades, however, these kinases were not activated unless the multicomponent signaling complex translocated from CD40 to the cytosol upon c-IAP1/2–induced degradation of TRAF3.
Abstract: Cytokine signaling is thought to require assembly of multicomponent signaling complexes at cytoplasmic segments of membrane-embedded receptors, in which receptor-proximal protein kinases are activated. Indeed, CD40, a tumor necrosis factor receptor (TNFR) family member, forms a complex containing adaptor molecules TRAF2 and TRAF3, ubiquitin-conjugating enzyme Ubc13, cellular inhibitor of apoptosis proteins 1 and 2 (c-IAP1/2), IκB kinase regulatory subunit IKKγ (also called NEMO), and mitogen-activated protein kinase (MAPK) kinase kinase MEKK1 upon ligation. TRAF2, Ubc13, and IKKγ were required for complex assembly and activation of MEKK1 and MAPK cascades. However, these kinases were not activated unless the multicomponent signaling complex translocated from CD40 to the cytosol upon c-IAP1/2–induced degradation of TRAF3. This two-stage signaling mechanism may apply to other innate immune receptors, accounting for spatial and temporal separation of MAPK and IKK signaling.
TL;DR: The data suggest that ASK1 is activated by APAP overdose, most likely via a mechanism involving thioredoxin-ASK1 dissociation, and that it plays a role in APAP-induced liver injury through JNK activation.
TL;DR: Using an epidermal-specific inducible knockdown mouse model, it is demonstrated that ΔNp63 proteins are essential for maintaining basement membrane integrity and terminal differentiation of keratinocytes and two target genes are identified that mediate these processes.
Abstract: Mice lacking p63, a single gene that encodes a group of transcription factors that either contain (TA) or lack (ΔN) a transactivation domain, fail to develop stratified epithelia as well as epithelial appendages and limbs. ΔNp63 isoforms are predominantly expressed during late embryonic and postnatal epidermal development, however, the function of these proteins remains elusive. Using an epidermal-specific inducible knockdown mouse model, we demonstrate that ΔNp63 proteins are essential for maintaining basement membrane integrity and terminal differentiation of keratinocytes. Furthermore, we have identified two ΔNp63α target genes that mediate these processes. We propose that ΔNp63α initially induces expression of the extracellular matrix component Fras1, which is required for maintaining the integrity of the epidermal–dermal interface at the basement membrane. Subsequently, induction of IκB kinase-α by ΔNp63α initiates epidermal terminal differentiation resulting in the formation of the spinous layer. Our data provide insights into the role of ΔNp63α in epidermal morphogenesis and homeostasis, and may contribute to our understanding of the pathogenic mechanisms underlying disorders caused by p63 mutations.
TL;DR: It is suggested that IKKβ inhibits the “classically” activated or M1 macrophage phenotype during infection through negative cross talk with the Stat1 pathway, which may represent a mechanism to prevent the over-exuberant activation of macrophages during infection and contribute to the resolution of inflammation.
Abstract: The nuclear factor kappaB (NF-kappaB) pathway plays a central role in inflammation and immunity. In response to proinflammatory cytokines and pathogen-associated molecular patterns, NF-kappaB activation is controlled by IkappaB kinase (IKK)beta. Using Cre/lox-mediated gene targeting of IKKbeta, we have uncovered a tissue-specific role for IKKbeta during infection with group B streptococcus. Although deletion of IKKbeta in airway epithelial cells had the predicted effect of inhibiting inflammation and reducing innate immunity, deletion of IKKbeta in the myeloid lineage unexpectedly conferred resistance to infection that was associated with increased expression of interleukin (IL)-12, inducible nitric oxide synthase (NOS2), and major histocompatibility complex (MHC) class II by macrophages. We also describe a previously unknown role for IKKbeta in the inhibition of signal transducer and activator of transcription (Stat)1 signaling in macrophages, which is critical for IL-12, NOS2, and MHC class II expression. These studies suggest that IKKbeta inhibits the "classically" activated or M1 macrophage phenotype during infection through negative cross talk with the Stat1 pathway. This may represent a mechanism to prevent the over-exuberant activation of macrophages during infection and contribute to the resolution of inflammation. This establishes a new role for IKKbeta in the regulation of macrophage activation with important implications in chronic inflammatory disease, infection, and cancer.
TL;DR: A series of small molecules JIP1 mimics that function as substrate competitive inhibitors of JNK are reported, one of which, BI-78D3, dose-dependently inhibits the phosphorylation of J NK substrates both in vitro and in cell.
Abstract: JNK is a stress-activated protein kinase that modulates pathways implicated in a variety of disease states. JNK-interacting protein-1 (JIP1) is a scaffolding protein that enhances JNK signaling by creating a proximity effect between JNK and upstream kinases. A minimal peptide region derived from JIP1 is able to inhibit JNK activity both in vitro and in cell. We report here a series of small molecules JIP1 mimics that function as substrate competitive inhibitors of JNK. One such compound, BI-78D3, dose-dependently inhibits the phosphorylation of JNK substrates both in vitro and in cell. In animal studies, BI-78D3 not only blocks JNK dependent Con A-induced liver damage but also restores insulin sensitivity in mouse models of type 2 diabetes. Our findings open the way for the development of protein kinase inhibitors targeting substrate specific docking sites, rather than the highly conserved ATP binding sites. In view of its favorable inhibition profile, selectivity, and ability to function in the cellular milieu and in vivo, BI-78D3 represents not only a JNK inhibitor, but also a promising stepping stone toward the development of an innovative class of therapeutics.
TL;DR: In murine models, inhibition of IKKβ-dependent NF-κB activation exacerbates acute inflammation, but attenuates chronic inflammatory disease in the intestinal tract, highlighting the striking context and tissue dependence of the proinflammatory and antiapoptotic functions of NF-σκB.
Abstract: NF-κB is a key transcriptional regulator of inflammatory responses, but also controls expression of prosurvival genes, whose products protect tissues from damage and may thus act indirectly in an antiinflammatory fashion. The variable importance of these two distinct NF-κB-controlled responses impacts the potential utility of NF-κB inhibition as a treatment strategy for intractable inflammatory conditions, such as inflammatory bowel disease. Here, we show in murine models that inhibition of IKKβ-dependent NF-κB activation exacerbates acute inflammation, but attenuates chronic inflammatory disease in the intestinal tract. Acute ulcerating inflammation is aggravated because of diminished NF-κB-mediated protection against epithelial cell apoptosis and delayed mucosal regeneration secondary to reduced NF-κB-dependent recruitment of inflammatory cells that secrete cytoprotective factors. In contrast, in IL-10-deficient mice, which serve as a model of chronic T cell-dependent colitis, ablation of IKKβ in the intestinal epithelium has no impact, yet IKKβ deficiency in myeloid cells attenuates inflammation and prolongs survival. These results highlight the striking context and tissue dependence of the proinflammatory and antiapoptotic functions of NF-κB. Our findings caution against the therapeutic use of IKKβ/NF-κB inhibitors in acute inflammatory settings dominated by cell loss and ulceration.
TL;DR: It is suggested that a TGFβ–Smad2/3–IKKα axis is a critical Smad4-independent regulator of keratinocyte proliferation and differentiation.
Abstract: Cell-cycle exit and differentiation of suprabasal epidermal keratinocytes require nuclear IκB kinase α (IKKα), but not its protein kinase activity. IKKα also is a suppressor of squamous cell carcinoma (SCC), but its mode of action remains elusive. Postulating that IKKα may serve as a transcriptional regulator in keratinocytes, we searched for cell-cycle-related genes that could illuminate this function. IKKα was found to control several Myc antagonists, including Mad1, Mad2, and Ovol1, through the association with TGFβ-regulated Smad2/3 transcription factors and is required for Smad3 recruitment to at least one of these targets. Surprisingly, Smad2/3-dependent Mad1 induction and keratinocyte differentiation are independent of Smad4, the almost universal coregulator of canonical TGFβ signaling. IKKα also is needed for nuclear accumulation of activated Smad2/3 in the epidermis, and Smad2/3 are required for epidermal differentiation. We suggest that a TGFβ–Smad2/3–IKKα axis is a critical Smad4-independent regulator of keratinocyte proliferation and differentiation.
TL;DR: In this paper, the IKK/nuclear factor-κB dependent microglia activation contributes to KA-induced hippocampal neuronal cell death in vivo through induction of inflammatory mediators.
Abstract: Microglial cells are activated during excitotoxin-induced neurodegeneration. However, the in vivo role of microglia activation in neurodegeneration has not yet been fully elucidated. To this end, we used Ikkβ conditional knockout mice (LysM-Cre/IkkβF/F) in which the Ikkβ gene is specifically deleted in cells of myeloid lineage, including microglia, in the CNS. This deletion reduced IκB kinase (IKK) activity in cultured primary microglia by up to 40% compared with wild-type (IkkβF/F), and lipopolysaccharide-induced proinflammatory gene expression was also compromised. Kainic acid (KA)-induced hippocampal neuronal cell death was reduced by 30% in LysM-Cre/IkkβF/F mice compared with wild-type mice. Reduced neuronal cell death was accompanied by decreased KA-induced glial cell activation and subsequent expression of proinflammatory genes such as tumour necrosis factor (TNF)-α and interleukin (IL)-1β. Similarly, neurons in organotypic hippocampal slice cultures (OHSCs) from LysM-Cre/IkkβF/F mouse brain were less susceptible to KA-induced excitotoxicity compared with wild-type OHSCs, due in part to decreased TNF-α and IL-1β expression. Based on these data, we concluded that IKK/nuclear factor-κB dependent microglia activation contributes to KA-induced hippocampal neuronal cell death in vivo through induction of inflammatory mediators.
TL;DR: This review focuses on how photonic energy and its primary cellular products are sensed and converted into the "language of cells"--signal reception and transduction.
TL;DR: Impaired tumor development correlated with decreased tumor initiation, which is associated with the production of reactive oxygen species, and lower levels of tumorigenesis were correlated with the decreased expression of cyclin D and CDK as well as decreased cell proliferation.
Abstract: c-Jun NH(2)-terminal kinase (JNK) links several cellular processes, including proliferation and survival, and is believed to be involved in carcinogenesis. However, the role of JNK in gastric tumorigenesis is unknown. Immunohistochemical analysis reveals that JNK is frequently activated in human gastric cancer tissue. We investigated whether JNK1, a major JNK isozyme, is involved in chemically induced gastric cancer development. Mice lacking JNK1 exhibited a marked decrease in gastric carcinogenesis induced by N-methyl-N-nitrosourea, relative to their wild-type counterparts. Impaired tumor development correlated with decreased tumor initiation, which is associated with the production of reactive oxygen species. We also found that lower levels of tumorigenesis were correlated with the decreased expression of cyclin D and CDK as well as decreased cell proliferation. Taken together, JNK seems to be involved in both tumor initiation and promotion and may be an attractive target for the prevention of gastric carcinogenesis.
TL;DR: This multifunctional protein is a key regulator of keratinocyte and epidermal differentiation and a critical suppressor of skin cancer.
Abstract: IκB kinase α (IKKα), one of the two catalytic subunits of the IKK complex involved in nuclear factor κB (NF-κB) activation, also functions as a molecular switch that controls epidermal differentiation. This unexpected function requires IKKα nuclear translocation but does not depend on its kinase activity, and is independent of NF-κB signalling. Ikkα–/– mice present with a hyperproliferative and undifferentiated epidermis characterized by complete absence of a granular layer and stratum corneum. Ikkα-deficient keratinocytes do not express terminal differentiation markers and continue to proliferate even when subjected to differentiation-inducing stimuli. This antiproliferative function of IKKα is also important for the suppression of squamous cell carcinogenesis. The exact mechanisms by which nuclear IKKα controls keratinocyte proliferation and differentiation remained mysterious for some time. Recent studies, however, have revealed that IKKα is a major cofactor in a TGFβ–Smad2/3 signalling pathway that is Smad4 independent. This pathway controls cell cycle withdrawal during keratinocyte terminal differentiation. Although these are not the only functions of nuclear IKKα, this multifunctional protein is a key regulator of keratinocyte and epidermal differentiation and a critical suppressor of skin cancer.
TL;DR: This work has generated a monoclonal antibody (mAb) that specifically recognizes K63-linked polyUb, but not any other isopeptide-linked (K6, K11, K27, K29, K33, or K48) polyUb or monoubiquitin.
Abstract: Modification of proteins by the addition of lysine (K)-63-linked polyubiquitin (polyUb) chains is suggested to play important roles in a variety of cellular events, including DNA repair, signal transduction, and receptor endocytosis. However, identifying such modifications in living cells is complex and cumbersome. We have generated a monoclonal antibody (mAb) that specifically recognizes K63-linked polyUb, but not any other isopeptide-linked (K6, K11, K27, K29, K33, or K48) polyUb or monoubiquitin. We demonstrate the sensitivity and specificity of this K63Ub-specific mAb to detect K63Ub-modified proteins in cell lysates by Western blotting and in cells by immunofluorescence, and K63Ub-modified TRAF6 and MEKK1 in vitro and ex vivo. This unique mAb will facilitate the analysis of K63-linked polyubiquitylation ex vivo and presents a strategy for the generation of similar reagents against other forms of polyUb.
01 Jan 2008
TL;DR: It is concluded that IKK/nuclear factor-kappaB dependent microglia activation contributes to KA-induced hippocampal neuronal cell death in vivo through induction of inflammatory mediators.
TL;DR: In SCCs that are unable to shuttle IKKα to the nucleus, defective TGF-β-induced growth arrest was rescued by introduction of a constitutively nuclear IKKβ variant, and results suggest that the tumor-suppressive activity of IKK α in stratified epithelia may be exerted in part via the T GF-β signaling pathway.
Abstract: The transforming growth factor type β-1 (TGF-β) signaling pathway is a major tumor suppressor during early carcinogenesis, and its growth-suppressive activity is commonly lost during early tumor progression. IκB kinase α (IKKα) also acts as a tumor suppressor in stratified epithelia, and its expression and nuclear localization are progressively down-regulated during malignant progression of squamous cell carcinoma (SCC) and acquisition of an invasive phenotype. A critical role for IKKα in TGF-β signaling in stratified epithelia was identified recently during normal keratinocyte differentiation, and both IKKα and components of the TGF-β signaling pathway are required for induction of antiproliferative Myc antagonists in such cells. We now describe that the interaction between IKKα and the TGF-β signaling pathway is also important in a subset of SCCs. In SCCs that are unable to shuttle IKKα to the nucleus, defective TGF-β-induced growth arrest was rescued by introduction of a constitutively nuclear IKKα variant. These results suggest that the tumor-suppressive activity of IKKα in stratified epithelia may be exerted in part via the TGF-β signaling pathway.
TL;DR: It is concluded that Nod2 contributes to the susceptibility to Y. pseudotuberculosis in mice and this resistance phenotype was lost in case of intraperitoneal infection.
Abstract: Nucleotide oligomerisation domain 2 (NOD2) is a component of the innate immunity known to be involved in the homeostasis of Peyer patches (PPs) in mice. However, little is known about its role during gut infection in vivo. Yersinia pseudotuberculosis is an enteropathogen causing gastroenteritis, adenolymphitis and septicaemia which is able to invade its host through PPs. We investigated the role of Nod2 during Y. pseudotuberculosis infection. Death was delayed in Nod2 deleted and Crohn's disease associated Nod2 mutated mice orogastrically inoculated with Y. pseudotuberculosis. In PPs, the local immune response was characterized by a higher KC level and a more intense infiltration by neutrophils and macrophages. The apoptotic and bacterial cell counts were decreased. Finally, Nod2 deleted mice had a lower systemic bacterial dissemination and less damage of the haematopoeitic organs. This resistance phenotype was lost in case of intraperitoneal infection. We concluded that Nod2 contributes to the susceptibility to Y. pseudotuberculosis in mice.
TL;DR: Results indicate that the IKKβ/NF‐κB pathway plays a previously unappreciated role in development of the sinusoidal vasculature in the fetal liver and additionally that this pathway is critical in the crosstalk between endothelial cells and hepatocytes during mouse development.
Abstract: The nuclear factor-kappaB (NF-kappaB) signaling pathway regulates cellular growth, survival, differentiation and development. In this study, the functions of IkappaB kinase (IKK)beta in angiogenesis during mouse development were examined. Conditional disruption of the Ikkbeta locus in endothelial cells using the well-characterized Tie2-Cre transgene resulted in embryonic lethality between embryonic day (E) 13.5 and E15.5. Examination of the mutant embryos revealed that while deletion of Ikkbeta occurred in endothelial cells throughout the embryo, only the vascular network in the fetal liver was affected. Disruption of the fetal liver vasculature was accompanied by decreased cell proliferation and increased apoptosis of hepatocytes, but hematopoiesis was not affected. Increased apoptosis was not observed outside of fetal liver in the mutant embryos. These results indicate that the IKKbeta/NF-kappaB pathway plays a previously unappreciated role in development of the sinusoidal vasculature in the fetal liver and additionally that this pathway is critical in the crosstalk between endothelial cells and hepatocytes during mouse development.
TL;DR: This study investigated the impact of NF-kappaB signalling on prion disease in mouse models with a central nervous system (CNS)-restricted elimination of IKKbeta or IKKgamma in nearly all neuroectodermal cells and in mice containing a non-phosphorylatable IKKalpha subunit (IKKalpha AA/AA).
Abstract: Prions induce highly typical histopathological changes including cell death, spongiosis and activation of glia, yet the molecular pathways leading to neurodegeneration remain elusive. Following prion infection, enhanced nuclear factor-kappaB (NF-kappaB) activity in the brain parallels the first pathological changes. The NF-kappaB pathway is essential for proliferation, regulation of apoptosis and immune responses involving induction of inflammation. The IkappaB kinase (IKK) signalosome is crucial for NF-kappaB signalling, consisting of the catalytic IKKalpha/IKKbeta subunits and the regulatory IKKgamma subunit. This study investigated the impact of NF-kappaB signalling on prion disease in mouse models with a central nervous system (CNS)-restricted elimination of IKKbeta or IKKgamma in nearly all neuroectodermal cells, including neurons, astrocytes and oligodendrocytes, and in mice containing a non-phosphorylatable IKKalpha subunit (IKKalpha AA/AA). In contrast to previously published data, the observed results showed no evidence supporting the hypothesis that impaired NF-kappaB signalling in the CNS impacts on prion pathogenesis.
01 Jan 2008
TL;DR: IjB kinase a (IKKa), one of the two catalytic subunits of the IKK complex involved in nuclear factor jB (NF-jB)activation, also functions as a molecular switch that con-trols epidermal differentiation.
Abstract: IjB kinase a (IKKa), one of the two catalytic subunits ofthe IKK complex involved in nuclear factor jB (NF-jB)activation, also functions as a molecular switch that con-trols epidermal differentiation. This unexpected functionrequires IKKa nuclear translocation but does not dependon its kinase activity, and is independent of NF-jB signal-ling. Ikka