Different modes of NF-κB/Rel activation in pancreatic lobules

2002 ◽  
Vol 283 (2) ◽  
pp. G270-G281 ◽  
Author(s):  
Hana Algül ◽  
Yusuke Tando ◽  
Michael Beil ◽  
Christoph K. Weber ◽  
Claus Von Weyhern ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Nuclear Factor Κb ◽  
Pancreatic Acinar Cells ◽  
Tubulin Polymerization ◽  
Nuclear Factor ◽  
Eukaryotic Transcription ◽  
Iκb Kinase ◽  
Factor Α ◽  
Transcription Factor Nuclear Factor ◽  
Necrosis Factor

The eukaryotic transcription factor nuclear factor-κB (NF-κB)/Rel is activated by a large variety of stimuli. It has been demonstrated that NF-κB/Rel is induced during the course of cerulein pancreatitis. Here, we show that NF-κB/Rel is differentially activated in pancreatic lobules. Cerulein induces NF-κB/Rel via activation of IκB kinase (IKK), which causes degradation of IκBα but not IκBβ. Tumor necrosis factor-α-mediated IKK activation leads to IκBα and IκBβ degradation. In contrast, oxidative stress induced by H2O2activates NF-κB/Rel independent of IKK activation and IκBα degradation; instead IκBα is phosphorylated on tyrosine. H2O2but not cerulein-mediated NF-κB/Rel activation can be blocked by stabilizing microtubules with Taxol. Inhibition of tubulin polymerization with nocodazole causes NF-κB/Rel activation in pancreatic lobules. These results propose three different pathways of NF-κB/Rel activation in pancreatic acinar cells. Furthermore, these data demonstrate that microtubules play a key role in IKK-independent NF-κB/Rel activation following oxidative stress.

scholarly journals Tumor-Induced Oxidative Stress Perturbs Nuclear Factor-κB Activity-Augmenting Tumor Necrosis Factor-α–Mediated T-Cell Death: Protection by Curcumin

2007 ◽  
Vol 67 (1) ◽  
pp. 362-370 ◽  
Author(s):  
Sankar Bhattacharyya ◽  
Debaprasad Mandal ◽  
Gouri Sankar Sen ◽  
Suman Pal ◽  
Shuvomoy Banerjee ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
T Cell ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Nuclear Factor Κb ◽  
Nuclear Factor ◽  
Factor Α ◽  
Necrosis Factor

scholarly journals The IKKβ Subunit of IκB Kinase (IKK) is Essential for Nuclear Factor κB Activation and Prevention of Apoptosis

1999 ◽  
Vol 189 (11) ◽  
pp. 1839-1845 ◽  
Author(s):  
Zhi-Wei Li ◽  
Wenming Chu ◽  
Yinling Hu ◽  
Mireille Delhase ◽  
Tom Deerinck ◽  
...  
Keyword(s):  
Interleukin 1 ◽  
Nuclear Factor Κb ◽  
Regulatory Subunit ◽  
Nuclear Factor ◽  
Catalytic Subunits ◽  
Iκb Kinase ◽  
Ikk Complex ◽  
Factor Α ◽  
Necrosis Factor

The IκB kinase (IKK) complex is composed of three subunits, IKKα, IKKβ, and IKKγ (NEMO). While IKKα and IKKβ are highly similar catalytic subunits, both capable of IκB phosphorylation in vitro, IKKγ is a regulatory subunit. Previous biochemical and genetic analyses have indicated that despite their similar structures and in vitro kinase activities, IKKα and IKKβ have distinct functions. Surprisingly, disruption of the Ikkα locus did not abolish activation of IKK by proinflammatory stimuli and resulted in only a small decrease in nuclear factor (NF)-κB activation. Now we describe the pathophysiological consequence of disruption of the Ikkβ locus. IKKβ-deficient mice die at mid-gestation from uncontrolled liver apoptosis, a phenotype that is remarkably similar to that of mice deficient in both the RelA (p65) and NF-κB1 (p50/p105) subunits of NF-κB. Accordingly, IKKβ-deficient cells are defective in activation of IKK and NF-κB in response to either tumor necrosis factor α or interleukin 1. Thus IKKβ, but not IKKα, plays the major role in IKK activation and induction of NF-κB activity. In the absence of IKKβ, IKKα is unresponsive to IKK activators.

I. TNF-induced liver injury

1998 ◽  
Vol 275 (3) ◽  
pp. G387-G392 ◽  
Author(s):  
Cynthia A. Bradham ◽  
Jörg Plümpe ◽  
Michael P. Manns ◽  
David A. Brenner ◽  
Christian Trautwein
Keyword(s):  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Nuclear Factor Κb ◽  
Hepatocyte Proliferation ◽  
Nuclear Factor ◽  
Normal Hepatocyte ◽  
Tnf Α ◽  
Factor Α ◽  
Transcription Factor Nuclear Factor ◽  
Necrosis Factor

Tumor necrosis factor-α (TNF-α) functions as a two-edged sword in the liver. TNF-α is required for normal hepatocyte proliferation during liver regeneration. It functions both as a comitogen and to induce the transcription factor nuclear factor-κB, which has antiapoptotic effects. On the other hand, TNF-α is the mediator of hepatotoxicity in many animal models, including those involving the toxins concanavalin A and lipopolysaccharide. TNF-α has also been implicated as an important pathogenic mediator in patients with alcoholic liver disease and viral hepatitis.

scholarly journals UXT is a novel and essential cofactor in the NF-κB transcriptional enhanceosome

2007 ◽  
Vol 178 (2) ◽  
pp. 231-244 ◽  
Author(s):  
Shaogang Sun ◽  
Yujie Tang ◽  
Xiwen Lou ◽  
Lianhui Zhu ◽  
Kai Yang ◽  
...  
Keyword(s):  
Prostate Cancer Cell ◽  
Hybrid Approach ◽  
Nuclear Factor Κb ◽  
Nuclear Factor ◽  
Human Prostate Cancer Cell ◽  
Expression Of Genes ◽  
Factor Α ◽  
Two Hybrid ◽  
Transcription Factor Nuclear Factor ◽  
Necrosis Factor

As a latent transcription factor, nuclear factor κB (NF-κB) translocates from the cytoplasm into the nucleus upon stimulation and mediates the expression of genes that are important in immunity, inflammation, and development. However, little is known about how it is regulated inside the nucleus. By a two-hybrid approach, we identify a prefoldin-like protein, ubiquitously expressed transcript (UXT), that is expressed predominantly and interacts specifically with NF-κB inside the nucleus. RNA interference knockdown of UXT leads to impaired NF-κB activity and dramatically attenuates the expression of NF-κB–dependent genes. This interference also sensitizes cells to apoptosis by tumor necrosis factor-α. Furthermore, UXT forms a dynamic complex with NF-κB and is recruited to the NF-κB enhanceosome upon stimulation. Interestingly, the UXT protein level correlates with constitutive NF-κB activity in human prostate cancer cell lines. The presence of NF-κB within the nucleus of stimulated or constitutively active cells is considerably diminished with decreased endogenous UXT levels. Our results reveal that UXT is an integral component of the NF-κB enhanceosome and is essential for its nuclear function, which uncovers a new mechanism of NF-κB regulation.

scholarly journals Macrophage-secreted cytokines drive pancreatic acinar-to-ductal metaplasia through NF-κB and MMPs

2013 ◽  
Vol 202 (3) ◽  
pp. 563-577 ◽  
Author(s):  
Geou-Yarh Liou ◽  
Heike Döppler ◽  
Brian Necela ◽  
Murli Krishna ◽  
Howard C. Crawford ◽  
...  
Keyword(s):  
Target Genes ◽  
Acinar Cells ◽  
Nuclear Factor Κb ◽  
Pancreatic Acinar Cells ◽  
Nuclear Factor ◽  
Signaling Mechanisms ◽  
Acinar To Ductal Metaplasia ◽  
Factor Α ◽  
Necrosis Factor

In response to inflammation, pancreatic acinar cells can undergo acinar-to-ductal metaplasia (ADM), a reprogramming event that induces transdifferentiation to a ductlike phenotype and, in the context of additional oncogenic stimulation, contributes to development of pancreatic cancer. The signaling mechanisms underlying pancreatitis-inducing ADM are largely undefined. Our results provide evidence that macrophages infiltrating the pancreas drive this transdifferentiation process. We identify the macrophage-secreted inflammatory cytokines RANTES and tumor necrosis factor α (TNF) as mediators of such signaling. Both RANTES and TNF induce ADM through activation of nuclear factor κB and its target genes involved in regulating survival, proliferation, and degradation of extracellular matrix. In particular, we identify matrix metalloproteinases (MMPs) as targets that drive ADM and provide in vivo data suggesting that MMP inhibitors may be efficiently applied to block pancreatitis-induced ADM in therapy.

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