The NF- B Family of Transcription Factors and Its Regulation

Oeckinghaus, Andrea; Ghosh, Sankar

doi:10.1101/cshperspect.a000034

Cited by 2,382 publications

(2,051 citation statements)

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“…Activation of the IKK complex is dependent on the phosphorylation of 2 serine residues in at least one of its subunits (Ser176/180 of IKKa or Ser177/181 of IKKb subunit; ref. 13). Therefore, we evaluated the activation status of the IKKa/b complex by Western blot analysis with a phosphospecific antibody that detects the endogenous levels of IKKa and IKKb only when phosphorylated at Ser176 and Ser180 or Ser177 and Ser181, respectively.…”

Section: Minocycline Blocks Ikba Kinase Activationmentioning

confidence: 99%

“…When stimulated by appropriate extracellular signals, IkBa is phosphorylated by inhibitor of IkB kinase (IKK), which results in proteasome-mediated degradation of IkBa. Then the active complex of NF-kB gets librated and translocates to nucleus to mediate transcription of its target genes (13). IKK complex is activated either through autophosphorylation or via phosphorylation by a series of mitogenactivated kinase kinase kinases (MAP3K) including TGFb-activated kinase-1 (TAK1).…”

Section: Introductionmentioning

confidence: 99%

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RETRACTED: Minocycline Targets the NF-κB Nexus through Suppression of TGF-β1-TAK1-IκB Signaling in Ovarian Cancer

Ataie-Kachoie

Badar

Morris

et al. 2013

Molecular Cancer Research

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Substantial evidence supports the critical role of NF-kB in ovarian cancer. Minocycline, a tetracycline, has been shown to exhibit beneficial effects in this malignancy through regulation of a cohort of genes that overlap significantly with the NF-kB transcriptome. Here, it was examined whether or not the molecular mechanism could be attributed to modulation of NF-kB signaling using a combination of in vitro and in vivo models. Minocycline suppressed constitutive NF-kB activation in OVCAR-3 and SKOV-3 ovarian carcinoma cells and was correlated with attenuation of IkBa kinase (IKK) activation, IkBa phosphorylation and degradation, and p65 phosphorylation and nuclear translocation. The inhibition of IKK was found to be associated with suppression of TGF-b-activated-kinase-1 (TAK1) activation and its dissociation from TAK1-binding-protein-1 (TAB1), an indispensable functional mediator between TGF-b and TAK1. Further studies demonstrated that minocycline downregulated TGF-b1 expression. Enforced TGF-b1 expression induced NF-kB activity, and minocycline rescued this effect. Consistent with this finding, TGF-b1 knockdown suppressed NF-kB activation and abrogated the inhibitory effect of minocycline on this transcription factor. These results suggest that the minocycline-induced suppression of NF-kB activity is mediated, in part, through inhibition of TGF-b1. Furthermore, the influence of minocycline on NF-kB pathway activation was examined in female nude mice harboring intraperitoneal OVCAR-3 tumors. Both acute and chronic administration of minocycline led to suppression of p65 phosphorylation and nuclear translocation accompanied by downregulation of NF-kB activity and endogenous protein levels of its target gene products. These data reveal the therapeutic potential of minocycline as an agent targeting the pro-oncogenic TGF-b-NF-kB axis in ovarian cancer.

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Section: Minocycline Blocks Ikba Kinase Activationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

RETRACTED: Minocycline Targets the NF-κB Nexus through Suppression of TGF-β1-TAK1-IκB Signaling in Ovarian Cancer

Ataie-Kachoie

Badar

Morris

et al. 2013

Molecular Cancer Research

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“…IKK␥ (also known as NEMO), a regulatory subunit of IKK, has been shown to play an essential role in functionally activating catalytic subunits of IKK (5,11,18,26,31,44). Since we found that IKK␤ was functionally associated with Nkx3.2-mediated NF-B activation, we next investigated whether NEMO is also involved in this process.…”

Section: Resultsmentioning

confidence: 99%

Exogenous Signal-Independent Nuclear IκB Kinase Activation Triggered by Nkx3.2 Enables Constitutive Nuclear Degradation of IκB-α in Chondrocytes

Yong

Choi

et al. 2011

Molecular and Cellular Biology

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NF-B is a multifunctional transcription factor involved in diverse biological processes. It has been well documented that NF-B can be activated in response to various stimuli. While signal-inducible NF-B activation mechanisms have been extensively characterized, exogenous signal-independent intrinsic NF-B activation processes remain poorly understood. Here we show that I B kinase ␤ (IKK␤) can be intrinsically activated in the nucleus by a homeobox protein termed Nkx3.2 in the absence of exogenous IKK-activating signals. We found that ubiquitin chain-dependent, but persistent, interactions between Nkx3.2 and NEMO (also known as IKK␥) can give rise to constitutive IKK␤ activation in the nucleus. Once the Nkx3.2-NEMO-IKK␤ complex is formed in the nucleus, IKK␤-induced Nkx3.2 phosphorylation at Ser148 and Ser168 allows ␤TrCP to be engaged to cause I B-␣ ubiquitination independent of I B-␣ phosphorylation at Ser32 and Ser36. Taken together, our results provide a novel molecular explanation as to how an intracellular factor such as Nkx3.2 can accomplish persistent nuclear IKK activation to enable intrinsic and constitutive degradation of I B in the nucleus in the absence of exogenous NF-B-activating signals, which, in turn, plays a role in chondrocyte viability maintenance.NF-B regulates expression of a variety of genes associated with immune responses, proliferation, differentiation, and apoptosis (21, 23, 39). Numerous studies have described in detail the molecular mechanisms of signal-dependent NF-B activation. In particular, it is well established that diverse NF-B-activating signals trigger I B kinase ␤ (IKK␤) activation in the cytoplasm to permit signal-dependent I B-␣ phosphorylation, which, in turn, causes its ubiquitination and proteasomal degradation, leading to 11,13,18,21,23,39). While these extensive studies pertain to the signal-inducible NF-B activation process, exogenous signal-independent intrinsic NF-B activation mechanisms are largely unknown.Nkx3.2 (also termed Bapx1) is initially expressed in chondrocyte precursor cells during development, and later, its expression is maintained in chondrocytes of various skeletal elements (19,20,25,29,37,47). We have previously demonstrated that Nkx3.2 supports chondrocyte survival by constitutively activating p65-RelA, leaving p105 and p100 NF-B unaffected (28). However, it remains to be understood how Nkx3.2, a nuclear homeobox protein, can indeed trigger constitutive I B degradation and give rise to intrinsic NF-B activation in chondrocytes in the absence of exogenous NF-Bactivating signals.It has been suggested that polyubiquitin chains play a role in creating multiprotein complexes in signal-inducible NF-B activation pathways (4,9,27,34,35,41,48). For instance, the ability of NEMO (also known as IKK␥) to recognize and interact with polyubiquitin chains has been shown to be critical for NEMO to establish functionally active IKK complexes in the cytoplasm in response to NF-B-activating signals (4,9,34,41,48). While these findings pertain to signal-inducible ev...

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“…To investigate the detailed mechanism involved in the repression of PP2Aca and PP2Acb transcription, we analyzed the potential binding sites of NF-kB or NF-kB downstream genes [28][29][30] in the 5 0 upstream regions of PP2Aca and PP2Acb by using Genomatix software. 31 In addition to NFkB itself, the potential binding sites of several transcription factors, which have been proven to be the target genes of the NF-kB pathway, were identified ( Figure 5G).…”

Section: Inflammatory Stimuli Repressed Pp2ac Expression In An Nf-kbmentioning

confidence: 99%

Inflammatory stimuli promote growth and invasion of pancreatic cancer cells through NF-κB pathway dependent repression of PP2Ac

et al. 2016

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Previous studies have indicated that inflammatory stimulation represses protein phosphatase 2A (PP2A), a well-known tumor suppressor. However, whether PP2A repression participates in pancreatic cancer progression has not been verified. We used lipopolysaccharide (LPS) and macrophage-conditioned medium (MCM) to establish in vitro inflammation models, and investigated whether inflammatory stimuli affect pancreatic cancer cell growth and invasion PP2A catalytic subunit (PP2Ac)-dependently. Via nude mouse models of orthotopic tumor xenografts and dibutyltin dichloride (DBTC)-induced chronic pancreatitis, we evaluated the effect of an inflammatory microenvironment on PP2Ac expression in vivo. We cloned the PP2Aca and PP2Acb isoform promoters to investigate the PP2Ac transcriptional regulation mechanisms. MCM accelerated pancreatic cancer cell growth; MCM and LPS promoted cell invasion. DBTC promoted xenograft growth and metastasis, induced tumor-associated macrophage infiltration, promoted angiogenesis, activated the nuclear factor-kB (NF-kB) pathway, and repressed PP2Ac expression. In vitro, LPS and MCM downregulated PP2Ac mRNA and protein. PP2Aca overexpression attenuated JNK, ERK, PKC, and IKK phosphorylation, and impaired LPS/MCM-stimulated cell invasion and MCM-promoted cell growth. LPS and MCM activated the NF-kB pathway in vitro. LPS and MCM induced IKK and IkB phosphorylation, leading to p65/RelA nuclear translocation and transcriptional activation. Overexpression of the dominant negative forms of IKKa attenuated LPS and MCM downregulation of PP2Ac, suggesting inflammatory stimuli repress PP2Ac expression NF-kB pathway-dependently. Luciferase reporter gene assay verified that LPS and MCM downregulated PP2Ac transcription through an NF-kB-dependent pathway. Our study presents a new mechanism in inflammation-driven cancer progression through NF-kB pathway-dependent PP2Ac repression.

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The NF- B Family of Transcription Factors and Its Regulation

Cited by 2,382 publications

References 105 publications

RETRACTED: Minocycline Targets the NF-κB Nexus through Suppression of TGF-β1-TAK1-IκB Signaling in Ovarian Cancer

RETRACTED: Minocycline Targets the NF-κB Nexus through Suppression of TGF-β1-TAK1-IκB Signaling in Ovarian Cancer

Exogenous Signal-Independent Nuclear IκB Kinase Activation Triggered by Nkx3.2 Enables Constitutive Nuclear Degradation of IκB-α in Chondrocytes

Inflammatory stimuli promote growth and invasion of pancreatic cancer cells through NF-κB pathway dependent repression of PP2Ac

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