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TBK1; TANK-binding kinase 1 (12q14.1)

Gene Summary

Gene:TBK1; TANK-binding kinase 1
Aliases: NAK, T2K
Location:12q14.1
Summary:The NF-kappa-B (NFKB) complex of proteins is inhibited by I-kappa-B (IKB) proteins, which inactivate NFKB by trapping it in the cytoplasm. Phosphorylation of serine residues on the IKB proteins by IKB kinases marks them for destruction via the ubiquitination pathway, thereby allowing activation and nuclear translocation of the NFKB complex. The protein encoded by this gene is similar to IKB kinases and can mediate NFKB activation in response to certain growth factors. [provided by RefSeq, Oct 2010]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:serine/threonine-protein kinase TBK1
HPRD
Source:NCBI
Updated:15 December, 2014

Gene
Ontology:

What does this gene/protein do?
Show (31)

Pathways:

What pathways are this gene/protein implicaed in?
- Toll-like receptor signaling pathway KEGG
Data from KEGG and BioCarta [BIOCARTA terms] via CGAP

Cancer Overview

Research Indicators

Publications Per Year (1989-2014)
Graph generated 15 December 2014 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Transfection
  • Western Blotting
  • Cell Survival
  • Cancer Gene Expression Regulation
  • Apoptosis
  • RNA Interference
  • p53 Protein
  • Transcription Factor RelA
  • Estrogen Receptor alpha
  • MCF-7 Cells
  • HeLa Cells
  • bcl-X Protein
  • siRNA
  • Transcription Factor RelB
  • Interleukin-8
  • Cell Proliferation
  • ras Proteins
  • Breast Cancer
  • Polymerase Chain Reaction
  • Protein Binding
  • I-kappa B Kinase
  • Non-Small Cell Lung Cancer
  • Inflammation
  • Chromosome 12
  • Lung Cancer
  • Transcriptional Activation
  • Interleukin-6
  • NF-kappa B
  • Transcription Factors
  • Phosphorylation
  • Signal Transduction
  • Cell Cycle
  • Protein-Serine-Threonine Kinases
  • VEGFA
  • ral GTP-Binding Proteins
  • Drug Resistance
  • Protein Kinase Inhibitors
  • Cervical Cancer
  • Proto-Oncogene Proteins c-rel
  • MicroRNAs
Tag cloud generated 15 December, 2014 using data from PubMed, MeSH and CancerIndex

Notable (4)

Scope includes mutations and abnormal protein expression.

Entity Topic PubMed Papers
Lung CancerTBK1 and Lung Cancer View Publications7
Breast CancerTBK1 and Breast Cancer View Publications4
Lung Cancer, Non-Small CellTBK1 and Non-Small Cell Lung Cancer View Publications3
Cervical CancerTBK1 and Cervical Cancer View Publications1

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Related Links

Latest Publications: TBK1 (cancer-related)

Kim HN, Kim DH, Kim EH, et al.
Sulforaphane inhibits phorbol ester-stimulated IKK-NF-κB signaling and COX-2 expression in human mammary epithelial cells by targeting NF-κB activating kinase and ERK.
Cancer Lett. 2014; 351(1):41-9 [PubMed] Related Publications
Sulforaphane, an isothiocyanate present in cruciferous vegetables, has been reported to possess anti-inflammatory and cancer chemopreventive properties. However, the molecular mechanisms by which sulforaphane suppresses inflammation and carcinogenesis are yet to be fully elucidated. Since the aberrant expression of cyclooxygenase-2 (COX-2) links inflammation and cancer, the present study was aimed to elucidate the mechanisms by which sulforaphane modulates COX-2 overexpression in human mammary epithelial (MCF-10A) cells stimulated with a prototypic tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). Treatment of MCF-10A cells with sulforaphane significantly inhibited TPA-induced expression of COX-2 protein and its mRNA transcript. Transient transfection of cells with deletion mutant constructs of COX-2 promoter revealed that the transcription factor nuclear factor-kappaB (NF-κB) plays a key role in TPA-induced COX-2 expression in MCF-10A cells. Pretreatment with sulforaphane significantly attenuated nuclear localization, DNA binding and the transcriptional activity of NF-κB through inhibition of phosphorylation and subsequent degradation of IκBα in MCF-10A cells stimulated with TPA. Sulforaphane also attenuated TPA-induced activation of IκB kinases (IKK), NF-κB-activating kinase (NAK) and extracellular signal-regulated kinase-1/2 (ERK1/2). Pharmacological inhibition of IKK or transient transfection of cells with dominant-negative mutant forms of this kinase abrogated TPA-induced NF-κB activation and COX-2 expression. In addition, the blockade of ERK1/2 activation negated the catalytic activity of IKKα, but not that of IKKβ, whereas silencing NAK by specific siRNA abrogated the IKKβ activity in TPA-treated cells. Taken together, sulforaphane inhibits TPA-induced NF-κB activation and COX-2 expression in MCF-10A cells by blocking two distinct signaling pathways mediated by ERK1/2-IKKα and NAK-IKKβ.

Related: Breast Cancer COX2 (PTGS2)


Deng T, Liu JC, Chung PE, et al.
shRNA kinome screen identifies TBK1 as a therapeutic target for HER2+ breast cancer.
Cancer Res. 2014; 74(7):2119-30 [PubMed] Related Publications
HER2(+) breast cancer is currently treated with chemotherapy plus anti-HER2 inhibitors. Many patients do not respond or relapse with aggressive metastatic disease. Therefore, there is an urgent need for new therapeutics that can target HER2(+) breast cancer and potentiate the effect of anti-HER2 inhibitors, in particular those that can target tumor-initiating cells (TIC). Here, we show that MMTV-Her2/Neu mammary tumor cells cultured as nonadherent spheres or as adherent monolayer cells select for stabilizing mutations in p53 that "immortalize" the cultures and that, after serial passages, sphere conditions maintain TICs, whereas monolayer cells gradually lose these tumorigenic cells. Using tumorsphere formation as surrogate for TICs, we screened p53-mutant Her2/Neu(+) tumorsphere versus monolayer cells with a lentivirus short hairpin RNA kinome library. We identified kinases such as the mitogen-activated protein kinase and the TGFβR protein family, previously implicated in HER2(+) breast cancer, as well as autophagy factor ATG1/ULK1 and the noncanonical IκB kinase (IKK), TANK-binding kinase 1 (TBK1), which have not been previously linked to HER2(+) breast cancer. Knockdown of TBK1 or pharmacologic inhibition of TBK1 and the related protein, IKKε, suppressed growth of both mouse and human HER2(+) breast cancer cells. TBK1/IKKε inhibition promoted cellular senescence by suppressing p65-NF-κB and inducing p16(Ink4a). In addition, TBK1/IKKε inhibition cooperated with lapatinib, a HER2/EGFR1-targeted drug, to accelerate apoptosis and kill HER2(+) breast cancer cells both in culture and in xenografts. Our results suggest that patients with HER2(+) breast cancer may benefit from anti-TBK1/IKKε plus anti-HER2 combination therapies and establish conditions that can be used to screen for additional TIC-specific inhibitors of HER2(+) breast cancer.

Related: Apoptosis Breast Cancer Lapatinib (Tyverb)


Selvakumar P, Owens TA, David JM, et al.
Epigenetic silencing of Na,K-ATPase β 1 subunit gene ATP1B1 by methylation in clear cell renal cell carcinoma.
Epigenetics. 2014; 9(4):579-86 [PubMed] Article available free on PMC after 01/04/2015 Related Publications
The Na,K-ATPase or sodium pump carries out the coupled extrusion of Na(+) and uptake of K(+) across the plasma membranes of cells of most higher eukaryotes. We have shown earlier that Na,K-ATPase-β 1 (NaK-β) protein levels are highly reduced in poorly differentiated kidney carcinoma cells in culture and in patients' tumor samples. The mechanism(s) regulating the expression of NaK-β in tumor tissues has yet to be explored. We hypothesized that DNA methylation plays a role in silencing the NaK-β gene (ATP1B1) expression in kidney cancers. In this study, to the best of our knowledge we provide the first evidence that ATP1B1 is epigenetically silenced by promoter methylation in both renal cell carcinoma (RCC) patients' tissues and cell lines. We also show that knockdown of the von Hippel-Lindau (VHL) tumor suppressor gene in RCC cell lines results in enhanced ATP1B1 promoter AT hypermethylation, which is accompanied by reduced expression of NaK-β. Furthermore, treatment with 5-Aza-2'-deoxycytidine rescued the expression of ATP1B1 mRNA as well as NaK-β protein in these cells. These data demonstrate that promoter hypermethylation is associated with reduced NaK-β expression, which might contribute to RCC initiation and/or disease progression.

Related: Azacitidine Kidney Cancer VHL


Zhang Z, Huang L, Wu Q, et al.
A recombinant trans-membrane protein hMnSOD-R9 inhibits the proliferation of cervical cancer cells in vitro.
Mol Cell Biochem. 2014; 385(1-2):79-86 [PubMed] Related Publications
Human manganese superoxide dismutase (hMnSOD) is a new type of cancer suppressor. Nonamer of arginine (R9) is an efficient protein transduction domain (PTD). The aim of the study was to improve the transduction efficiency of hMnSOD and investigate its activity in vitro. In this study, we designed, constructed, expressed, and purified a novel fusion protein containing the hMnSOD domain and R9 PTD (hMnSOD–R9). The DNA damaged by Fenton’s reagent was found to be significantly reduced when treated with hMnSOD–R9. hMnSOD–R9 fusion protein was successfully delivered into HeLa cells. The MTT assay showed that proliferation of various cancer cell lines were inhibited by hMnSOD–R9 in a dose-dependent manner. In addition, the cell cycle of HeLa cells was arrested at the sub-G0 phase by hMnSOD–R9. hMnSOD–R9 induced apoptosis of HeLa cells in a dose-dependent manner. With hMnSOD–R9 treatment, Bax, JNK, TBK1 gene expression was increased and STAT3 gene expression was gradually down-regulated in HeLa cells. We also found that apoptosis was induced by hMnSOD–R9 in HeLa cells via up-regulation of cleaved caspase-3 and down-regulation phospho-STAT3 pathway. These results indicated that hMnSOD–R9 may provide benefits to cervical cancer treatment.

Related: Apoptosis Cervical Cancer


Yang KM, Jung Y, Lee JM, et al.
Loss of TBK1 induces epithelial-mesenchymal transition in the breast cancer cells by ERα downregulation.
Cancer Res. 2013; 73(22):6679-89 [PubMed] Related Publications
Estrogen receptor α (ERα) is the pivotal regulator of proliferation and differentiation in mammary epithelia, where it serves as a crucial prognostic marker and therapeutic target in breast cancer. In this study, we show that the loss of the kinase TANK-binding kinase 1 (TBK1) induces epithelial-mesenchymal transition in ERα-positive breast cancer cells by downregulating ERα expression. TBK1 was overexpressed in ERα-positive breast cancers, where it was associated with distant metastasis-free survival in patients, whereas it was underexpressed in ERα-negative breast cancers. TBK1 silencing decreased expression of epithelial markers and increased expression of mesenchymal markers in ERα-positive breast cancer cells, enhancing tumor growth and lung metastasis in vivo in a manner associated with downregulation of ERα expression. Mechanistically, TBK1 silencing reduced FOXO3A binding to the ERα promoter by inducing the translocation of phosphorylated FOXO3A from the nucleus to the cytoplasm. Thus, our results indicate that the loss of TBK1 expression parallels the loss of ERα expression, in turn helping drive an aggressive breast cancer phenotype.

Related: Breast Cancer


Kim JY, Welsh EA, Oguz U, et al.
Dissection of TBK1 signaling via phosphoproteomics in lung cancer cells.
Proc Natl Acad Sci U S A. 2013; 110(30):12414-9 [PubMed] Article available free on PMC after 01/04/2015 Related Publications
TANK-binding kinase 1 (TBK1) has emerged as a novel therapeutic target for unspecified subset of lung cancers. TBK1 reportedly mediates prosurvival signaling by activating NF-κB and AKT. However, we observed that TBK1 knockdown also decreased viability of cells expressing constitutively active NF-κB and interferon regulatory factor 3. Basal phospho-AKT level was not reduced after TBK1 knockdown in TBK1-sensitive lung cancer cells, implicating that TBK1 mediates unknown survival mechanisms. To gain better insight into TBK1 survival signaling, we searched for altered phosphoproteins using mass spectrometry following RNAi-mediated TBK1 knockdown. In total, we identified 2,080 phosphoproteins (4,621 peptides), of which 385 proteins (477 peptides) were affected after TBK1 knockdown. A view of the altered network identified a central role of Polo-like kinase 1 (PLK1) and known PLK1 targets. We found that TBK1 directly phosphorylated PLK1 in vitro. TBK1 phosphorylation was induced at mitosis, and loss of TBK1 impaired mitotic phosphorylation of PLK1 in TBK1-sensitive lung cancer cells. Furthermore, lung cancer cell sensitivity to TBK1 was highly correlated with sensitivity to pharmacological PLK inhibition. We additionally found that TBK1 knockdown decreased metadherin phosphorylation at Ser-568. Metadherin was associated with poor outcome in lung cancer, and loss of metadherin caused growth inhibition and apoptosis in TBK1-sensitive lung cancer cells. These results collectively revealed TBK1 as a mitosis regulator through activation of PLK1 and also suggested metadherin as a putative TBK1 downstream effector involved in lung cancer cell survival.

Related: Lung Cancer Signal Transduction


Karim R, Tummers B, Meyers C, et al.
Human papillomavirus (HPV) upregulates the cellular deubiquitinase UCHL1 to suppress the keratinocyte's innate immune response.
PLoS Pathog. 2013; 9(5):e1003384 [PubMed] Article available free on PMC after 01/04/2015 Related Publications
Persistent infection of basal keratinocytes with high-risk human papillomavirus (hrHPV) may cause cancer. Keratinocytes are equipped with different pattern recognition receptors (PRRs) but hrHPV has developed ways to dampen their signals resulting in minimal inflammation and evasion of host immunity for sustained periods of time. To understand the mechanisms underlying hrHPV's capacity to evade immunity, we studied PRR signaling in non, newly, and persistently hrHPV-infected keratinocytes. We found that active infection with hrHPV hampered the relay of signals downstream of the PRRs to the nucleus, thereby affecting the production of type-I interferon and pro-inflammatory cytokines and chemokines. This suppression was shown to depend on hrHPV-induced expression of the cellular protein ubiquitin carboxyl-terminal hydrolase L1 (UCHL1) in keratinocytes. UCHL1 accomplished this by inhibiting tumor necrosis factor receptor-associated factor 3 (TRAF3) K63 poly-ubiquitination which lead to lower levels of TRAF3 bound to TANK-binding kinase 1 and a reduced phosphorylation of interferon regulatory factor 3. Furthermore, UCHL1 mediated the degradation of the NF-kappa-B essential modulator with as result the suppression of p65 phosphorylation and canonical NF-κB signaling. We conclude that hrHPV exploits the cellular protein UCHL1 to evade host innate immunity by suppressing PRR-induced keratinocyte-mediated production of interferons, cytokines and chemokines, which normally results in the attraction and activation of an adaptive immune response. This identifies UCHL1 as a negative regulator of PRR-induced immune responses and consequently its virus-increased expression as a strategy for hrHPV to persist.

Related: Cytokines Signal Transduction Cervical Cancer


Conlon J, Burdette DL, Sharma S, et al.
Mouse, but not human STING, binds and signals in response to the vascular disrupting agent 5,6-dimethylxanthenone-4-acetic acid.
J Immunol. 2013; 190(10):5216-25 [PubMed] Article available free on PMC after 01/04/2015 Related Publications
Vascular disrupting agents such as 5,6-dimethylxanthenone-4-acetic acid (DMXAA) represent a novel approach for cancer treatment. DMXAA has potent antitumor activity in mice and, despite significant preclinical promise, failed human clinical trials. The antitumor activity of DMXAA has been linked to its ability to induce type I IFNs in macrophages, although the molecular mechanisms involved are poorly understood. In this study, we identify stimulator of IFN gene (STING) as a direct receptor for DMXAA leading to TANK-binding kinase 1 and IFN regulatory factor 3 signaling. Remarkably, the ability to sense DMXAA was restricted to murine STING. Human STING failed to bind to or signal in response to DMXAA. Human STING also failed to signal in response to cyclic dinucleotides, conserved bacterial second messengers known to bind and activate murine STING signaling. Collectively, these findings detail an unexpected species-specific role for STING as a receptor for an anticancer drug and uncover important insights that may explain the failure of DMXAA in clinical trials for human cancer.

Related: Cancer Prevention and Risk Reduction Signal Transduction


Higuchi T, Nakayama T, Arao T, et al.
SOX4 is a direct target gene of FRA-2 and induces expression of HDAC8 in adult T-cell leukemia/lymphoma.
Blood. 2013; 121(18):3640-9 [PubMed] Related Publications
Previously, we have shown that an AP-1 family member, FRA-2, is constitutively expressed in adult T-cell leukemia/lymphoma (ATL) and, together with JUND, upregulates CCR4 and promotes ATL cell growth. Among the identified potential target genes of FRA-2/JUND was SOX4. Here, we examine the expression and function of SOX4 in ATL. SOX4 was indeed consistently expressed in primary ATL cells. FRA-2/JUND efficiently activated the SOX4 promoter via an AP-1 site. Knockdown of SOX4 expression by small interfering RNA (siRNA) strongly suppressed cell growth of ATL cell lines. Microarray analyses revealed that SOX4 knockdown reduced the expression of genes such as germinal center kinase related (GCKR), NAK-associated protein 1 (NAP1), and histone deacetylase 8 (HDAC8). We confirmed consistent expression of GCKR, NAP1, and HDAC8 in primary ATL cells. We also showed direct activation of the HDAC8 promoter by SOX4. Furthermore, siRNA knockdown of GCKR, NAP1, and HDAC8 each significantly suppressed cell growth of ATL cell lines. Taken together, we have revealed an important oncogenic cascade involving FRA-2/JUND and SOX4 in ATL, which leads to the expression of genes such as GCKR, NAP1, and HDAC8.

Related: FOSL2


Mijatovic T, Kiss R
Cardiotonic steroids-mediated Na+/K+-ATPase targeting could circumvent various chemoresistance pathways.
Planta Med. 2013; 79(3-4):189-98 [PubMed] Related Publications
Many cancer patients fail to respond to chemotherapy because of the intrinsic resistance of their cancer to pro-apoptotic stimuli or the acquisition of the multidrug resistant phenotype during chronic treatment. Previous data from our groups and from others point to the sodium/potassium pump (the Na+/K+-ATPase, i.e., NaK) with its highly specific ligands (i.e., cardiotonic steroids) as a new target for combating cancers associated with dismal prognoses, including gliomas, melanomas, non-small cell lung cancers, renal cell carcinomas, and colon cancers. Cardiotonic steroid-mediated Na+/K+-ATPase targeting could circumvent various resistance pathways. The most probable pathways include the involvement of Na+/K+-ATPase β subunits in invasion features and Na+/K+-ATPase α subunits in chemosensitisation by specific cardiotonic steroid-mediated apoptosis and anoïkis-sensitisation; the regulation of the expression of multidrug resistant-related genes; post-translational regulation, including glycosylation and ubiquitinylation of multidrug resistant-related proteins; c-Myc downregulation; hypoxia-inducible factor downregulation; NF-κB downregulation and deactivation; the inhibition of the glycolytic pathway with a reduction of intra-cellular ATP levels and an induction of non-apoptotic cell death. The aims of this review are to examine the various molecular pathways by which the NaK targeting can be more deleterious to biologically aggressive cancer cells than to normal cells.

Related: Apoptosis Cancer Prevention and Risk Reduction Signal Transduction


Zhang P, Wu S, Li L, et al.
Adjuvant PIKA protects hepatoma cells from dengue virus infection by promoting a TBK-1-dependent innate immune response.
Arch Virol. 2013; 158(4):829-38 [PubMed] Related Publications
Our study presents a first investigation of the effect of the adjuvant PIKA on dengue virus (DENV) replication. PIKA pretreatment decreased the levels of DENV serotype 2 (DENV2) mRNA, protein and viral particles in the hepatoma cell line HepG2. Treatment with PIKA simultaneously with DENV2 infection, but not after infection, resulted in a protective effect. Significant induction of type I and type III interferons (IFNs), as well as interferon-stimulated genes was detected in PIKA-pretreated cells. Neutralization of IFN-β partially restored the replication levels of DENV2 in PIKA-pretreated cells, suggesting that IFN-β is one of the mediators involved in the antiviral action of PIKA. Additionally, blockade of TBK-1 signaling largely restored the IFN induction and viral suppression effects mediated by PIKA, further illustrating that PIKA plays its anti-DENV role by promoting innate immunity. These findings suggest that PIKA is an attractive agent to be used in the prevention of DENV diseases.

Related: Liver Cancer Signal Transduction


To SK, Zeng JZ, Wong AS
Nur77: a potential therapeutic target in cancer.
Expert Opin Ther Targets. 2012; 16(6):573-85 [PubMed] Related Publications
INTRODUCTION: The orphan nuclear receptor Nur77 (also known as NR4A1, NGFIB, TR3, TIS1, NAK-1, or N10) is a unique transcription factor encoded by an immediate early gene. Nur77 signaling is deregulated in many cancers and constitutes an important molecule for drug targeting.
AREAS COVERED: Nur77 as a versatile transcription factor that displays distinct dual roles in cell proliferation and apoptosis. In addition, several recent insights into Nur77's non-genomic signaling through its physical interactions with various signaling proteins and its phosphorylation-dependent regulation will be highlighted. The possible mechanisms by which Nur77 supports carcinogenesis and specific examples in different human cancers will be summarized. Different approaches to target Nur77 using mimetics, natural products, and synthetic compounds are also described.
EXPERT OPINION: These latest findings shed light on the novel roles of Nur77 as an exploitable target for new cancer therapeutics. Further work which focuses on a more complete understanding of the Nur77 interactome as well as how the different networks of Nur77 functional interactions are orchestrated in a stimulus or context-specific way will aid the development of more selective, non-toxic approaches for targeting Nur77 in future.

Related: Cancer Prevention and Risk Reduction


Baldwin AS
Regulation of cell death and autophagy by IKK and NF-κB: critical mechanisms in immune function and cancer.
Immunol Rev. 2012; 246(1):327-45 [PubMed] Related Publications
The cellular response to survive or to undergo death is fundamental to the benefit of the organism, and errors in this process can lead to autoimmunity and cancer. The transcription factor nuclear factor κB (NF-κB) functions to block cell death through transcriptional induction of genes encoding anti-apoptotic and antioxidant proteins. This is essential for survival of activated cells of the immune system and for cells undergoing a DNA damage response. In Ras-transformed cells and tumors as well as other cancers, NF-κB functions to suppress apoptosis--a hallmark of cancer. Critical prosurvival roles for inhibitor of NF-κB kinase (IKK) family members, including IKKε and TBK1, have been reported, which are both NF-κB-dependent and -independent. While the roles of NF-κB in promoting cell survival in lymphocytes and in cancers is relatively clear, evidence has been presented that NF-κB can promote cell death in particular contexts. Recently, IKK was shown to play a critical role in the induction of autophagy, a metabolic response typically associated with cell survival but which can lead to cell death. This review provides an historical perspective, along with new findings, regarding the roles of the IKK and NF-κB pathways in regulating cell survival.

Related: Cancer Prevention and Risk Reduction Signal Transduction TP53


Kanai R, Zaupa C, Sgubin D, et al.
Effect of γ34.5 deletions on oncolytic herpes simplex virus activity in brain tumors.
J Virol. 2012; 86(8):4420-31 [PubMed] Article available free on PMC after 01/04/2015 Related Publications
The ICP34.5 protein of herpes simplex virus (HSV) is involved in many aspects of viral pathogenesis; promoting neurovirulence, inhibiting interferon-induced shutoff of protein synthesis, interacting with PCNA and TBK1, inhibiting dendritic cell (DC) maturation, and binding to Beclin 1 to interfere with autophagy. Because of its key role in neuropathogenicity, the γ34.5 gene is deleted in all oncolytic HSVs (oHSVs) currently in clinical trial for treating malignant gliomas. Unfortunately, deletion of γ34.5 attenuates virus replication in cancer cells, especially human glioblastoma stem cells (GSCs). To develop new oHSVs for use in the brain and that replicate in GSCs, we explored the effect of deleting the γ34.5 Beclin 1 binding domain (BBD). To ensure cancer selectivity and safety, we inactivated the ICP6 gene (UL39, large subunit of ribonucleotide reductase), constructing ICP6 mutants with different γ34.5 genotypes: Δ68HR-6, intact γ34.5; Δ68H-6, γ34.5 BBD deleted; and 1716-6, γ34.5 deleted. Multimutated Δ68H-6 exhibited minimal neuropathogenicity in HSV-1-susceptible mice, as opposed to Δ68H and Δ68HR-6. It replicated well in human glioma cell lines and GSCs, effectively killing cells in vitro and prolonging survival of mice bearing orthotopic brain tumors. In contrast, 1716 and 1716-6 barely replicated in GSCs. Infection of glioma cells with Δ68H-6 and 1716-6 induced autophagy and increased phosphorylation of eIF2α, while inhibition of autophagy, by Beclin 1 short hairpin RNA (shRNA) knockdown or pharmacological inhibition, had no effect on virus replication or phosphorylated eIF2α (p-eIF2α) levels. Thus, Δ68H-6 represents a new oHSV vector that is safe and effective against a variety of brain tumor models.


Mahajan K, Mahajan NP
PI3K-independent AKT activation in cancers: a treasure trove for novel therapeutics.
J Cell Physiol. 2012; 227(9):3178-84 [PubMed] Article available free on PMC after 01/04/2015 Related Publications
AKT/PKB serine threonine kinase, a critical signaling molecule promoting cell growth and survival pathways, is frequently dysregulated in many cancers. Although phosphatidylinositol-3-OH kinase (PI3K), a lipid kinase, is well characterized as a major regulator of AKT activation in response to a variety of ligands, recent studies highlight a diverse group of tyrosine (Ack1/TNK2, Src, PTK6) and serine/threonine (TBK1, IKBKE, DNAPKcs) kinases that activate AKT directly to promote its pro-proliferative signaling functions. While some of these alternate AKT activating kinases respond to growth factors, others respond to inflammatory and genotoxic stimuli. A common theme emerging from these studies is that aberrant or hyperactivation of these alternate kinases is often associated with malignancy. Consequently, evaluating the use of small molecular inhibitors against these alternate AKT activating kinases at earlier stages of cancer therapy may overcome the pressing problem of drug resistance surfacing especially in patients treated with PI3K inhibitors.

Related: Cancer Prevention and Risk Reduction Signal Transduction


Saitoh Y, Martínez Bruyn VJ, Uota S, et al.
Overexpression of NF-κB inducing kinase underlies constitutive NF-κB activation in lung cancer cells.
Lung Cancer. 2010; 70(3):263-70 [PubMed] Related Publications
The present study investigates roles for NF-κB inducing kinase (NIK) in constitutive NF-κB activation in lung cancer cells. A wealth of evidence showed that NF-κB is often constitutively activated in human cancer cells, including non-small cell lung cancer tissue specimens and cell lines, which may lead to deregulated apoptosis and enhanced resistance of tumor cells to chemotherapy. However, the mechanisms of NF-κB activation in lung cancer cells remain largely unknown. We report here that NF-κB inducing kinase (NIK) is aberrantly expressed at the pre-translational level in non-small cell lung cancer (NSCLC) cell lines. Depletion of NIK by RNA interference remarkably diminished nuclear NF-κB DNA binding activity and reporter gene expression. NIK depletion induced apoptosis in A549 cells, reduced the matrix metalloproteinase 9 (MMP-9) and survivin mRNA expression and affected efficiency of anchorage-independent H1299 cell growth, suggesting a role for NIK in the manifestation of oncogenic phenotype. These results indicate that NIK plays a key role in constitutive NF-κB activation in NSCLC cells and implicate NIK as a molecular target for lung cancer therapy.

Related: Apoptosis Non-Small Cell Lung Cancer Lung Cancer MMP9: matrix metallopeptidase 9 BIRC5


Barbie DA, Tamayo P, Boehm JS, et al.
Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1.
Nature. 2009; 462(7269):108-12 [PubMed] Article available free on PMC after 01/04/2015 Related Publications
The proto-oncogene KRAS is mutated in a wide array of human cancers, most of which are aggressive and respond poorly to standard therapies. Although the identification of specific oncogenes has led to the development of clinically effective, molecularly targeted therapies in some cases, KRAS has remained refractory to this approach. A complementary strategy for targeting KRAS is to identify gene products that, when inhibited, result in cell death only in the presence of an oncogenic allele. Here we have used systematic RNA interference to detect synthetic lethal partners of oncogenic KRAS and found that the non-canonical IkappaB kinase TBK1 was selectively essential in cells that contain mutant KRAS. Suppression of TBK1 induced apoptosis specifically in human cancer cell lines that depend on oncogenic KRAS expression. In these cells, TBK1 activated NF-kappaB anti-apoptotic signals involving c-Rel and BCL-XL (also known as BCL2L1) that were essential for survival, providing mechanistic insights into this synthetic lethal interaction. These observations indicate that TBK1 and NF-kappaB signalling are essential in KRAS mutant tumours, and establish a general approach for the rational identification of co-dependent pathways in cancer.

Related: Apoptosis Lung Cancer Cancer Prevention and Risk Reduction Signal Transduction


Péant B, Diallo JS, Dufour F, et al.
Over-expression of IkappaB-kinase-epsilon (IKKepsilon/IKKi) induces secretion of inflammatory cytokines in prostate cancer cell lines.
Prostate. 2009; 69(7):706-18 [PubMed] Related Publications
BACKGROUND: Elevated inflammatory cytokine levels in serum have been associated with advanced stage metastasis-related morbidity in prostate cancer. Several studies have shown that IL-6 and IL-8 can accelerate the growth of human prostate cancer cell lines. Previous studies, in murine embryonic fibroblasts, have shown that Ikappa-B kinase-epsilon (IKKepsilon/IKKi)-deficiency results in the reduction of lipopolysaccharide-mediated expression of IL-6.
RESULTS: In this study, we report that over-expression of IKKepsilon in hormone-sensitive 22Rv1 and LNCaP prostate cancer cells induces the secretion of several inflammatory cytokines including IL-6 and IL-8. Both of these cytokines are secreted by hormone-refractory PC-3 prostate cancer cells and IKKepsilon knock-down in these cells correlates with a strong decrease in IL-6 secretion. Furthermore, we demonstrate that IKKepsilon over-expression does not induce the activation of the IKKepsilon classical targets NF-kappaB and IRF-3, two transcription factors involved in the regulation of several cytokines. Finally, we observe that high IKKepsilon expression results in its nuclear translocation, a phenomena that is TBK1-independent.
CONCLUSIONS: This study identifies IKKepsilon as a potential prostate cancer gene that may favor chronic inflammation and create a tumor-supporting microenvironment that promotes prostate cancer progression, particularly by the induction of IL-6 secretion that may act as a positive growth factor in prostate cancer.

Related: Prostate Cancer


Nakayama H, Yoshida A, Nakamura Y, et al.
Clinical significance of BRAF (V600E) mutation and Ki-67 labeling index in papillary thyroid carcinomas.
Anticancer Res. 2007 Sep-Oct; 27(5B):3645-9 [PubMed] Related Publications
BACKGROUND: Activating mutations of the BRAF gene have recently been reported in thyroid carcinomas. In particular, V600E mutation is highly prevalent in papillary thyroid carcinoma (PTC).
PATIENTS AND METHODS: In this study, the BRAF (V600E) mutation in 54 PTCs was investigated and the relationship between the BRAF mutation and clinicopathological features such as age, gender, tumor size, extrathyroid extension, lymph node metastasis, and distant metastasis was analyzed. Additionally, Ki-67 labeling index (LI) was determined to evaluate tumor cell proliferative activity.
RESULTS: The BRAF mutation was detected in 26 (65%) of 40 primary and 12 (85.7%) of 14 recurrent PTCs. The BRAF mutation was significantly related to older age (57.4 vs. 43.1 years, p=0.012), extrathyroid extension (76.9% vs. 35.7%, p=0.026), and lymph node metastasis (88.5% vs. 57.1%, p=0.044). Moreover, the mean Ki-67 LI was significantly higher in BRAF-positive patients than in BRAF-negative patients (1.01% vs. 0.135%, p=0.014). The BRAF mutation was common in PTCs classified as advanced TNM stage. Eighteen of 20 (90%) patients in TNM stages III and IV were positive for this gene mutation. Similarly, the BRAF mutation was investigated in 14 recurrent PTCs and was detected in 85.7% (12 of 14). The BRAF mutation was also common in patients with regional lymph node recurrence.
CONCLUSION: These results suggest that PTCs with BRAF (V600E) mutation are more aggressive than those with wildtype BRAF. This mutation may be important for predicting a worse prognosis in patients with PTC.

Related: MKI67 BRAF gene Thyroid Cancer


Korherr C, Gille H, Schäfer R, et al.
Identification of proangiogenic genes and pathways by high-throughput functional genomics: TBK1 and the IRF3 pathway.
Proc Natl Acad Sci U S A. 2006; 103(11):4240-5 [PubMed] Article available free on PMC after 01/04/2015 Related Publications
A genome-wide phenotype screen was used to identify factors and pathways that induce proliferation of human umbilical vein endothelial cells (HUVEC). HUVEC proliferation is a recognized marker for factors that modulate vascularization. Screening "hits" included known proangiogenic factors, such as VEGF, FGF1, and FGF2 and additional factors for which a direct association with angiogenesis was not previously described. These include the kinase TBK1 as well as Toll-like receptor adaptor molecule and IFN regulatory factor 3. All three proteins belong to one signaling pathway that mediates induction of gene expression, including a mixture of secreted factors, which, in concert, mediate proliferative activity toward endothelial cells. TBK1 as the "trigger" of this pathway is induced under hypoxic conditions and expressed at significant levels in many solid tumors. This pattern of expression and the decreased expression of angiogenic factors in cultured cells upon RNA-interference-mediated ablation suggests that TBK1 is important for vascularization and subsequent tumor growth and a target for cancer therapy.

Related: Cancer Prevention and Risk Reduction Signal Transduction


Messager M, Carrière C, Bertagna X, de Keyzer Y
RT-PCR analysis of corticotroph-associated genes expression in carcinoid tumours in the ectopic-ACTH syndrome.
Eur J Endocrinol. 2006; 154(1):159-66 [PubMed] Related Publications
OBJECTIVE: ACTH is frequently produced in non-pituitary tumours, leading to the ectopic-ACTH syndrome, but the molecular mechanisms of its expression remain obscure. This study was aimed at understanding the transcription mechanisms of the ACTH-precursor gene in carcinoid tumours of the lung or thymus.
DESIGN: Transcripts coding for a series of corticotroph-associated transcription factor genes were detected, together with markers of the corticotroph phenotype. We studied a series of 41 carcinoid tumours including 15 with proven ectopic-ACTH syndrome.
METHODS: Specific RT-PCR reactions were designed for each gene including alternatively spliced isoforms.
RESULTS: The markers of the corticotroph phenotype were detected in all ACTH-positive tumours. Expression of the Tpit and Pitx1 genes were not restricted to ACTH-positive tumours but were also detected in many ACTH-negative carcinoids. Only a subset of ACTH-negative tumours expressed NAK-1/Nur77, and NeuroD1 expression was detected in approximately 50% of the tumours regardless of their secretory status. The glucocorticoid receptor alpha was detected in every tumour in contrast to its beta isoform detectable in a few tumours only. Chicken ovalbumin upstream promoter-transcription factor 1 (COUP-TF1) and peroxisome proliferator-activated receptor (PPAR) gamma2 were expressed in 50% of the tumours of each group whereas PPARgamma1 was expressed in almost every tumour.
CONCLUSIONS: ACTH-positive carcinoids do not share a characteristic expression pattern of the corticotroph-associated transcription factor genes, suggesting that the transcriptional mechanisms of the ACTH-precursor gene differ from those in normal pituitary corticotrophs. Expression of Tpit and Pitx1 genes in most carcinoids suggests that some aspects of the pituitary corticotroph phenotype may belong to general carcinoid differentiation.

Related: Gastrointestinal Carcinoid Tumours PPARG gene


Pedra JH, Sukumaran B, Carlyon JA, et al.
Modulation of NB4 promyelocytic leukemic cell machinery by Anaplasma phagocytophilum.
Genomics. 2005; 86(3):365-77 [PubMed] Related Publications
Anaplasma phagocytophilum is a gram-negative obligate intracellular bacterium that persists within neutrophils. We assessed the impact of A. phagocytophilum infection in NB4 promyelocytic leukemic cells using high-density oligoarray, two-dimensional differential gel electrophoresis and liquid chromatography-mass spectrometry. Our Affymetrix data revealed that A. phagocytophilum altered the expression of transcription factors, cell adhesion molecules, signal transduction genes, and proinflammatory cytokines. However, the expression of Toll-like receptors, MYD88, RNF36, IRF3, and TBK1 and inhibitors of the NF-kappaB gene was not altered. A. phagocytophilum infection also altered the apoptotic program of NB4 cells and resulted in increased transcription of antiapoptotic genes (MCL1 and BFL1). The transcription and translation of iron-metabolism genes (light polypeptide ferritin chain, transferrin, and the transferrin receptor) were significantly altered, suggesting a possible link between A. phagocytophilum infection and iron metabolism. Our study clearly demonstrates multifactorial effects of A. phagocytophilum infection on NB4 promyelocytic leukemic cell machinery.

Related: Apoptosis Signal Transduction


Shishodia S, Koul D, Aggarwal BB
Cyclooxygenase (COX)-2 inhibitor celecoxib abrogates TNF-induced NF-kappa B activation through inhibition of activation of I kappa B alpha kinase and Akt in human non-small cell lung carcinoma: correlation with suppression of COX-2 synthesis.
J Immunol. 2004; 173(3):2011-22 [PubMed] Related Publications
The cyclooxygenase 2 (COX-2) inhibitor celecoxib (also called celebrex), approved for the treatment of colon carcinogenesis, rheumatoid arthritis, and other inflammatory diseases, has been shown to induce apoptosis and inhibit angiogenesis. Because NF-kappa B plays a major role in regulation of apoptosis, angiogenesis, carcinogenesis, and inflammation, we postulated that celecoxib modulates NF-kappa B. In the present study, we investigated the effect of this drug on the activation of NF-kappa B by a wide variety of agents. We found that celecoxib suppressed NF-kappa B activation induced by various carcinogens, including TNF, phorbol ester, okadaic acid, LPS, and IL-1 beta. Celecoxib inhibited TNF-induced I kappa B alpha kinase activation, leading to suppression of I kappa B alpha phosphorylation and degradation. Celecoxib suppressed both inducible and constitutive NF-kappa B without cell type specificity. Celecoxib also suppressed p65 phosphorylation and nuclear translocation. Akt activation, which is required for TNF-induced NF-kappa B activation, was also suppressed by this drug. Celecoxib also inhibited the TNF-induced interaction of Akt with I kappa B alpha kinase (IKK). Celecoxib abrogated the NF-kappa B-dependent reporter gene expression activated by TNF, TNF receptor, TNF receptor-associated death domain, TNF receptor-associated factor 2, NF-kappa B-inducing kinase, and IKK, but not that activated by p65. The COX-2 promoter, which is regulated by NF-kappa B, was also inhibited by celecoxib, and this inhibition correlated with suppression of TNF-induced COX-2 expression. Besides NF-kappa B, celecoxib also suppressed TNF-induced JNK, p38 MAPK, and ERK activation. Thus, overall, our results indicate that celecoxib inhibits NF-kappa B activation through inhibition of IKK and Akt activation, leading to down-regulation of synthesis of COX-2 and other genes needed for inflammation, proliferation, and carcinogenesis.

Related: Non-Small Cell Lung Cancer Lung Cancer AKT1 TNF


Lee BP, Rushlow WJ, Chakraborty C, Lala PK
Differential gene expression in premalignant human trophoblast: role of IGFBP-5.
Int J Cancer. 2001; 94(5):674-84 [PubMed] Related Publications
Tumorigenesis results from genetic alterations that occur in a stepwise manner giving rise to cells with increasingly cancer-like characteristics. We used in vitro propagated first trimester human extravillous trophoblast (EVT) cells to identify genetic changes responsible for the transition of the EVT from a normal to premalignant stage. The model used consisted of a normal invasive EVT (HTR8) cell line and its premalignant derivative (RSVT2/C) generated by transfection with the SV40 Tag and selected using a forced crisis regimen. RSVT2/C display increased proliferative, migratory and invasive behavior, unresponsiveness to anti-proliferative and anti-invasive signals of TGFbeta and a deficiency in gap junctional intercellular communication. These cells, however, were unable to form colonies on soft agar or tumors in nude mice and are thus defined as premalignant. Differential display revealed 18 gene sequences, 7 with unknown and 11 with known identity, showing altered expression between the normal HTR8 and premalignant RSVT2/C cell lines. The known sequences include the potential tumor suppressors insulin-like growth factor binding protein (IGFBP)-5 and fibronectin (FN) and potential protooncogenes such as chromokinesin (KIF4), alternative splicing factor (SF2), dynein, DNA polymerase epsilon (DNApol epsilon) and NF-kappaB activating kinase (NAK). The role of the remaining 4 genes upregulated in the premalignant EVT is presently unknown and these are FK506 binding protein (FKBP) 25, histone protein (HP1Hs)-gamma, nucleoporin (Nup) 155 and an 82 kDa acidic human protein. The functional role of IGFBP-5 was examined in the control of proliferation, migration and invasiveness of RSVT2/C cells measured in vitro. IGFBP-5 alone had no effect on these properties of RSVT2/C cells. Furthermore, unlike normal EVT cells, RSVT2/C cells exhibited refractoriness to the migration stimulating signals of IGF-II, which was explained by the loss or downregulation of the IGF type 2 receptor (IGF-R2). RSVT2/C cells, however, expressed the IGF type 1 receptor (IGF-R1) and responded to IGF-I by increased proliferation. This response was blocked with increasing concentrations of IGFBP-5. These results suggest that the loss of IGFBP-5 and possibly IGF-R2, both of which can sequester IGF-I from IGF-R1, permits unhindered proliferation of the premalignant EVT in an IGF-I rich environment of the fetal-maternal interface. The functions of the other differentially expressed genes, some of which are essential for cell cycle progression or cell survival require further investigation.

Related: IGF2


Gürel S, Dolar E, Yerci O, et al.
Expression of p53 protein and prognosis in gastric carcinoma.
J Int Med Res. 1999 Mar-Apr; 27(2):85-9 [PubMed] Related Publications
A study was carried out to assess whether p53 expression is related to tumour type, grade or pathological characteristics, or to prognosis, in gastric cancer. Immunohistochemical studies were performed to detect p53 protein in sections from 55 consecutive gastrectomy or partial gastrectomy specimens. Tumours were classified for T-stage, histopathological grade and pathological characteristics. Immunohistochemical staining detected p53 protein in 11 (19%) of the 55 specimens. There was no statistically significant difference between patients with p53 positively staining tumours and patients with p53 negatively staining tumours with regard to tumour grade, stage or pathological characteristics (lymph-node infiltration, depth of invasion, necrosis, or necrosis of vessels). Survival time was statistically significantly lower in patients with positively staining tumours (mean survival times 12.0 and 23.4 months, respectively). These results suggest that expression of p53 protein is related to poor prognosis in gastric carcinoma.

Related: Stomach Cancer Gastric Cancer TP53


Gürel S, Yerci O, Filiz G, et al.
High expression of multidrug resistance-1 (MDR-1) and its relationship with multiple prognostic factors in gastric carcinomas in patients in Turkey.
J Int Med Res. 1999 Mar-Apr; 27(2):79-84 [PubMed] Related Publications
Drug resistance remains a major problem in the treatment of gastric cancer. In Turkey, gastric carcinoma is the second most common cancer and, because the rate of early diagnosis is low, chemotherapy plays an important role in the treatment of the disease. We aimed to investigate expression of the multidrug resistance-1 gene (MDR-1) and its relationship with multiple prognostic factors in gastric cancers. Between 1996 and 1998, a total of 55 patients (37 men and 19 women; median age 55 years) were studied. Sections from specimens of gastric carcinomas were immunohistochemically stained to detect P-glycoprotein (which is associated with MDR-1 expression). We found MDR-1 expression in 48 (87%) of the patients. None of the multiple prognostic factors, including histological type of tumour, correlated with expression of MDR-1. Patients who had low MDR-1 expression had better survival. We conclude that the expression of MDR-1 in gastric cancer is high in Turkey, and this may be related to poor prognosis.

Related: Stomach Cancer Gastric Cancer


Gürel S, Dolar E, Yerci O, et al.
The relationship between c-erbB-2 oncogene expression and clinicopathological factors in gastric cancer.
J Int Med Res. 1999 Mar-Apr; 27(2):74-8 [PubMed] Related Publications
Gastric carcinoma is one of the most common carcinomas and a leading cause of death from cancer in Turkey. The relationship between clinicopathological features of the disease and oncogenes is under investigation. In this retrospective study we investigated the relationships between expression of c-erbB-2 oncoprotein and grade, stage and pathological characteristics of the tumour, and prognosis. Formalin-fixed, paraffin-embedded tissue sections were prepared from gastrectomy specimens from 55 patients with gastric carcinoma. The tissue sections were stained immunohistochemically to reveal c-erbB-2 protein. Six (10%) of the tumours stained positively for c-erbB-2 protein. There was no statistically significant association (P > 0.5) between c-erbB-2 staining and tumour grade, stage or pathological characteristics (necrosis, lymph-node infiltration), or between staining and prognosis. The results suggest that overexpression of c-erb-B-2 protein is not related to the pathological characteristics of the tumour in gastric carcinoma and is not an important prognostic indicator.

Related: ERBB2 (HER2) Stomach Cancer Gastric Cancer


Elbel M, Carl S, Spaderna S, Iftner T
A comparative analysis of the interactions of the E6 proteins from cutaneous and genital papillomaviruses with p53 and E6AP in correlation to their transforming potential.
Virology. 1997; 239(1):132-49 [PubMed] Related Publications
Common necessity for all papillomaviruses is to induce DNA synthesis in quiescent cells. This is commonly achieved by the E7 gene product, which interferes with the function of members of the retinoblastoma family controlling transition from the G1-phase to the S-phase of the cell cycle. Uncontrolled entry into S-phase activates, however, negative growth control signals which have to be bypassed to achieve production of progeny viruses. In addition to inherent activities of the E7 protein, high risk genital types encode an E6 protein that overcomes p53-mediated G1-arrest and apoptosis in concert with the cellular factor E6AP by targeting p53 for the enhanced ubiquitin-dependent degradation. The key question, which of these functions of genital E6 and E7 proteins is responsible for the carcinogenic phenotype, is still not completely answered. In contrast to high risk genital types no immortalizing or transforming activities have been found for the E7 proteins of the high risk cutaneous HPV8 and 47. On the other hand the ability of the E6 protein to transform established rodent fibroblasts seems to be a property shared by high risk genital and cutaneous types. To examine the existence of a common E6-mediated transforming pathway for both virus groups we compared the properties of the cutaneous E6 proteins with already known functions of E6 proteins of genital viruses. For this we analyzed the E6 proteins of low nak and high risk cutaneous and genital papillomaviruses with respect to cell transformation, to their abilities to bind, degradate, and influence the activity of human p53, and to bind E6AP. The results of our study demonstrate a clear lack of interaction between the transforming E6 proteins of HPV1 and HPV8 and both cellular proteins p53 and E6AP. In contrast, we found E6AP-independent binding of HPV16 E6 and HPV6 E6 to p53, although both proteins were different in their transforming potential. Of all four proteins investigated, only HPV16 E6 was able to bind to p53 and E6AP and to induce degradation of the p53 protein in the reticulocyte system. When we investigated in frame deletion mutants of the E6 protein of HPV16 for their abilities to bind to p53 or E6AP, degradate, and inhibit the transactivation function of p53 and to transform rodent fibroblasts, no correlation between the different activities could be found. Mutants still able to bind p53 and E6AP lacked transforming ability and other mutants that were transformation-competent were deficient in p53 and E6AP bindings.

Related: TP53


Joshi-Barve SS, Rangnekar VV, Sells SF, Rangnekar VM
Interleukin-1-inducible expression of gro-beta via NF-kappa B activation is dependent upon tyrosine kinase signaling.
J Biol Chem. 1993; 268(24):18018-29 [PubMed] Related Publications
Interleukin-1 (IL-1) induces programmed growth arrest in human melanoma cells, A375-C6. IL-1 action in these cells is associated with induction of a cell type-specific immediate-early (IE) gene expression program characterized by strong, rapid, and sustained induction of gro-alpha and gro-beta, but transient induction of c-jun, IRG-9, and NAK-1, and lack of induction of c-myc. With the exception of gro-alpha and gro-beta, these IE genes are also associated with growth-stimulatory responses in the melanoma cells, suggesting that the gro-genes may play key roles in the growth arrest action of the cytokine. To elucidate the early intracellular signals associated with IL-1 action, we are studying the second messenger signals and transcription factors required for induction of gro-genes. Here, we present evidence that IL-1-inducible gro-gene expression is dependent on tyrosine kinase signaling. Using gel retardation and transient expression assays, we show that IL-1 causes protein tyrosine phosphorylation-dependent activation of NF-kappa B enhancer binding protein, which then induces transcription of the gro-genes via an NF-kappa B site located 76 base pairs upstream from the cap site. IL-1-activated protein tyrosine phosphorylation is also required for gro-gene induction in human cervical carcinoma cells, HeLa; human fibroblast cells, WI-38; and mouse fibroblast cells, L929. Thus, in diverse cell types, IL-1 induces gro-genes via tyrosine kinase-dependent signals.

Related: CXCL1 Melanoma Signal Transduction


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Cite this page: Cotterill SJ. TBK1, Cancer Genetics Web: http://www.cancerindex.org/geneweb/TBK1.htm Accessed: date

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