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https://www.readbyqxmd.com/read/27845762/recent-progress-in-the-molecular-recognition-and-therapeutic-importance-of-interleukin-1-receptor-associated-kinase-4
#1
REVIEW
Mahesh Chandra Patra, Sangdun Choi
Toll-like receptors (TLRs) are the most upstream pattern recognition receptors in the cell, which detect pathogen associated molecular patterns and initiate signal transduction, culminating in the transcription of pro-inflammatory cytokines and antiviral interferon. Interleukin-1 receptor-associated kinase 4 (IRAK4) is a key mediator in TLR (except for TLR3) and interleukin-1 receptor signaling pathways. The loss of kinase function of IRAK4 is associated with increased susceptibility to various pathogens, while its over-activation causes autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, and cancer...
November 13, 2016: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/27579619/i%C3%AE%C2%BAb%C3%AE-an-emerging-player-in-cancer
#2
Marie Willems, Nadège Dubois, Lucia Musumeci, Vincent Bours, Pierre A Robe
IκBζ, an atypical member of the nuclear IκB family of proteins, is expressed at low levels in most resting cells, but is induced upon stimulation of Toll-like/IL-1 receptors through an IRAK1/IRAK4/NFκB-dependent pathway. Like its homolog Bcl3, IκBζ can regulate the transcription of a set of inflamatory genes through its association with the p50 or p52 subunits of NF-κB. Long studied as a key component of the immune response, IκBζ emerges as an important regulator of inflammation, cell proliferation and survival...
August 26, 2016: Oncotarget
https://www.readbyqxmd.com/read/26293885/the-architecture-of-the-tir-domain-signalosome-in-the-toll-like-receptor-4-signaling-pathway
#3
Emine Guven-Maiorov, Ozlem Keskin, Attila Gursoy, Carter VanWaes, Zhong Chen, Chung-Jung Tsai, Ruth Nussinov
Activated Toll-like receptors (TLRs) cluster in lipid rafts and induce pro- and anti-tumor responses. The organization of the assembly is critical to the understanding of how these key receptors control major signaling pathways in the cell. Although several models for individual interactions were proposed, the entire TIR-domain signalosome architecture has not been worked out, possibly due to its complexity. We employ a powerful algorithm, crystal structures and experimental data to model the TLR4 and its cluster...
August 21, 2015: Scientific Reports
https://www.readbyqxmd.com/read/25521277/3-3-diindolylmethane-attenuates-lps-mediated-acute-liver-failure-by-regulating-mirnas-to-target-irak4-and-suppress-toll-like-receptor-signalling
#4
S Tomar, M Nagarkatti, P S Nagarkatti
BACKGROUND AND PURPOSE: Acute liver failure (ALF) is a severe and potentially lethal clinical syndrome. 3,3'-Diindolylmethane (DIM) is a natural plant-derived compound with anti-cancer activities. Recently, DIM has also been shown to have anti-inflammatory properties. Here, we tested the hypothesis that DIM would suppress endotoxin-induced ALF. EXPERIMENTAL APPROACH: We investigated the therapeutic potential of DIM in a mouse model of D-galactosamine/Lipopolysaccharide (GalN/LPS)-induced ALF...
April 2015: British Journal of Pharmacology
https://www.readbyqxmd.com/read/24973222/a-coding-irak2-protein-variant-compromises-toll-like-receptor-tlr-signaling-and-is-associated-with-colorectal-cancer-survival
#5
Hui Wang, Sinead M Flannery, Sabine Dickhöfer, Stefanie Huhn, Julie George, Andriy V Kubarenko, Jesus Lascorz, Melanie Bevier, Joschka Willemsen, Tica Pichulik, Clemens Schafmayer, Marco Binder, Bénédicte Manoury, Søren R Paludan, Marta Alarcon-Riquelme, Andrew G Bowie, Asta Försti, Alexander N R Weber
Within innate immune signaling pathways, interleukin-1 receptor-associated kinases (IRAKs) fulfill key roles downstream of multiple Toll-like receptors and the interleukin-1 receptor. Although human IRAK4 deficiency was shown to lead to severe immunodeficiency in response to pyogenic bacterial infection during childhood, little is known about the role of human IRAK2. We here identified a non-synonymous IRAK2 variant, rs35060588 (coding R214G), as hypofunctional in terms of NF-κB signaling and Toll-like receptor-mediated cytokine induction...
August 15, 2014: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/24965109/high-mobility-group-box1-hmgb1-released-from-cancer-cells-induces-the-expression-of-pro-inflammatory-cytokines-in-peritoneal-fibroblasts
#6
Anna Abe, Takeshi Kuwata, Chisako Yamauchi, Youichi Higuchi, Atsushi Ochiai
High Mobility Group Box1 protein (HMGB1), one of the mediators of inflammation, is associated with tumorigenesis. The HMGB1-Receptor for advanced glycation end-products (RAGE) in gastric adenocarcinoma tissues promoted gastric cancer growth, however, there are no reports concerning the relationship between the expression of HMGB1 in gastric cancer and cancer-related inflammation. Fibroblasts exist most abundantly on cancer tissue where inflammation occurs. So, we studied the effects of HMGB1 released from cancer cells on the fibroblasts...
June 2014: Pathology International
https://www.readbyqxmd.com/read/24379523/irak1-4-targeted-anti-inflammatory-action-of-caffeic-acid
#7
Woo Seok Yang, Deok Jeong, Young-Su Yi, Jae Gwang Park, Hyohyun Seo, Sang Hyun Moh, Sungyoul Hong, Jae Youl Cho
Caffeic acid (CA) is a phenolic compound that is frequently present in fruits, grains, and dietary supplements. Although CA has been reported to display various biological activities such as anti-inflammatory, anti-cancer, anti-viral, and anti-oxidative effects, the action mechanism of CA is not yet fully elucidated. In this study, the anti-inflammatory action mechanism of CA was examined in lipopolysaccharide (LPS) treated macrophages (RAW264.7 cells) and HCl/EtOH-induced gastritis. CA was found to diminish nitric oxide (NO) and prostaglandin E2 (PGE2) production in LPS-stimulated RAW264...
2013: Mediators of Inflammation
https://www.readbyqxmd.com/read/24194738/irak4-and-tlr3-sequence-variants-may-alter-breast-cancer-risk-among-african-american-women
#8
Susan T Yeyeodu, Lacreis R Kidd, Gabriela M Oprea-Ilies, Brian G Burns, Tiva T Vancleave, Joong-Youn Shim, K Sean Kimbro
Mounting evidence suggests that imbalances in immune regulation contribute to cell transformation. Women of African descent are an understudied group at high risk for developing aggressive breast cancer (BrCa). Therefore, we examined the role of 16 innate immune single nucleotide polymorphisms (SNPs) in relation to BrCa susceptibility among 174 African-American women in Atlanta, GA, USA. SNPs were examined in germ-line DNA collected from 102 BrCa patients and 72 women with benign nodules using SNPstream methodology...
2013: Frontiers in Immunology
https://www.readbyqxmd.com/read/23657238/toll-like-receptor-associated-sequence-variants-and-prostate-cancer-risk-among-men-of-african-descent
#9
E N Rogers, D Z Jones, N C Kidd, S Yeyeodu, G Brock, C Ragin, M Jackson, N McFarlane-Anderson, M Tulloch-Reid, K Sean Kimbro, L R Kidd
Recent advances demonstrate a relationship between chronic/recurrent inflammation and prostate cancer (PCA). Among inflammatory regulators, toll-like receptors (TLRs) have a critical role in innate immune responses. However, it remains unclear whether variant TLR genes influence PCA risk among men of African descent. Therefore, we evaluated the impact of 32 TLR-associated single-nucleotide polymorphisms (SNPs) on PCA risk among African Americans and Jamaicans. SNP profiles of 814 subjects were evaluated using Illumina's Veracode genotyping platform...
September 2013: Genes and Immunity
https://www.readbyqxmd.com/read/23591012/a-kinome-wide-sirna-screen-identifies-multiple-roles-for-protein-kinases-in-hypoxic-stress-adaptation-including-roles-for-irak4-and-gak-in-protection-against-apoptosis-in-vhl-renal-carcinoma-cells-despite-activation-of-the-nf-%C3%AE%C2%BAb-pathway
#10
Jing Pan, Jing Zhang, Andrew Hill, Peter Lapan, Steve Berasi, Brian Bates, Christopher Miller, Steven Haney
Hypoxia induces changes to cancer cells that make them more resistant to treatment. We have looked at signaling pathways that facilitate these changes by screening the human kinome for effects on hypoxic responses in SW480 colon cancer cells. Hits identified in the screen were examined for effects on multiple molecular responses to hypoxia, including the endoplasmic reticulum stress and DNA damage responses in colon, melanoma, and renal cancer lines. To validate the hits from the small interfering RNA studies, we developed cell lines expressing stable short hairpin RNAs (shRNAs) in the A498 renal carcinoma cell line...
August 2013: Journal of Biomolecular Screening
https://www.readbyqxmd.com/read/22359464/are-toll-like-receptor-gene-polymorphisms-associated-with-prostate-cancer
#11
Anton G Kutikhin, Arseniy E Yuzhalin
The suggestion that there is a connection between chronic intraprostatic inflammation and prostate cancer was declared some years ago. As Toll-like receptors (TLRs) are the key players in the processes of chronic intraprostatic inflammation, there is a hypothesis that TLR gene polymorphisms may be associated with prostate cancer risk. Although a number of comprehensive studies have been conducted on large samples in various countries, reliable connections between these single nucleotide polymorphisms and prostate cancer risk, stage, grade, aggressiveness, ability to metastasize, and mortality have not been detected...
2012: Cancer Management and Research
https://www.readbyqxmd.com/read/19826413/tlr4-signaling-induced-by-lipopolysaccharide-or-paclitaxel-regulates-tumor-survival-and-chemoresistance-in-ovarian-cancer
#12
M Szajnik, M J Szczepanski, M Czystowska, E Elishaev, M Mandapathil, E Nowak-Markwitz, M Spaczynski, T L Whiteside
Toll-like receptors (TLRs) expressed on immune cells trigger inflammatory responses. TLRs are also expressed on ovarian cancer (OvCa) cells, but the consequences of signaling by the TLR4/MyD88 pathway in these cells are unclear. Here, TLR4 and MyD88 expression in OvCa tissues (n=20) and cell lines (OVCAR3, SKOV3, AD10, A2780 and CP70) was evaluated by reverse transcriptase-PCR, western blots and immunohistochemistry. Cell growth, apoptosis, nuclear factor-kappaB (NF-kappaB) translocation, IRAK4 and TRIF expression and cJun phosphorylation were measured following tumor cell exposure to the TLR4 ligands, lipopolysaccharide (LPS) or paclitaxel (PTX)...
December 10, 2009: Oncogene
https://www.readbyqxmd.com/read/19706770/identification-of-novel-gene-amplifications-in-breast-cancer-and-coexistence-of-gene-amplification-with-an-activating-mutation-of-pik3ca
#13
Mitsutaka Kadota, Misako Sato, Beverly Duncan, Akira Ooshima, Howard H Yang, Natacha Diaz-Meyer, Sheryl Gere, Shun-Ichiro Kageyama, Junya Fukuoka, Takuya Nagata, Kazuhiro Tsukada, Barbara K Dunn, Lalage M Wakefield, Maxwell P Lee
To identify genetic events that characterize cancer progression, we conducted a comprehensive genetic evaluation of 161 primary breast tumors. Similar to the "mountain-and-hill" view of mutations, gene amplification also shows high- and low-frequency alterations in breast cancers. The frequently amplified genes include the well-known oncogenes ERBB2, FGFR1, MYC, CCND1, and PIK3CA, whereas other known oncogenes that are amplified, although less frequently, include CCND2, EGFR, FGFR2, and NOTCH3. More importantly, by honing in on minimally amplified regions containing three or fewer genes, we identified six new amplified genes: POLD3, IRAK4, IRX2, TBL1XR1, ASPH, and BRD4...
September 15, 2009: Cancer Research
https://www.readbyqxmd.com/read/19217767/targeting-protein-kinases-for-the-development-of-anti-inflammatory-drugs
#14
REVIEW
Philip Cohen
In recent years, protein kinases have become the pharmaceutical industry's most studied class of drug target, and some 10 protein kinase inhibitors have so far been approved for the treatment of cancer. However, whether safe drugs that modulate protein kinase activities can also be developed for the treatment of chronic diseases, where they may need to be taken for decades, is an issue that is still unresolved. A number of compounds that inhibit the p38alpha MAPK have entered clinical trials for the treatment of rheumatoid arthritis and psoriasis, but side effects have prevented their progression to Phase III clinical trials...
April 2009: Current Opinion in Cell Biology
https://www.readbyqxmd.com/read/17567943/signaling-pathways-leading-to-the-activation-of-ikk-and-mapk-by-thymosin-alpha1
#15
Xiao Peng, Ping Zhang, Xin Wang, Justin Chan, Mingwei Zhu, Meisheng Jiang, Cynthia Tuthill, Yinsheng Wan, Ana Maria Dragoi, Wen-Ming Chu
Thymosin alpha 1 (Talpha1) has therapeutic potential in the treatment of infectious diseases and cancer. However, the exact molecular pathways for Talpha1 action are not fully understood. We found that Talpha1 induces the production of interleukin-6 (IL-6), IL-10, and IL-12 in murine bone marrow-derived macrophages (BMDMs) through IKK and MAPK pathways. Talpha1 triggers the activation of AP-1 and the phosphorylation of JNK and p38. Inhibition of p38 impairs IL-6 production in response to Talpha1. Further, TRAF6 is involved in the activation of JNK and IRAK4 is involved for the activation of IKK and PKCzeta in a Talpha1-induced system...
September 2007: Annals of the New York Academy of Sciences
https://www.readbyqxmd.com/read/16537705/interactions-of-sequence-variants-in-interleukin-1-receptor-associated-kinase4-and-the-toll-like-receptor-6-1-10-gene-cluster-increase-prostate-cancer-risk
#16
COMPARATIVE STUDY
Jielin Sun, Fredrik Wiklund, Fang-Chi Hsu, Katarina Bälter, S Lilly Zheng, Jan-Erik Johansson, Baoli Chang, Wennuan Liu, Tao Li, Aubrey R Turner, Liwu Li, Ge Li, Hans-Olov Adami, William B Isaacs, Jianfeng Xu, Henrik Grönberg
Chronic or recurrent inflammation has been suggested as a causal factor in several human malignancies, including prostate cancer. Genetic predisposition is also a strong risk factor in the development of prostate cancer. In particular, Toll-like receptors (TLR), especially the TLR6-1-10 gene cluster, are involved in prostate cancer development. Interleukin-1 receptor-associated kinases (IRAK) 1 and 4 are critical components in the TLR signaling pathway. In this large case-control study, we tested two hypotheses: (a) sequence variants in IRAK1 and IRAK4 are associated with prostate cancer risk and (b) sequence variants in IRAK1/4 and TLR1-6-10 interacts and confers a stronger risk to prostate cancer...
March 2006: Cancer Epidemiology, Biomarkers & Prevention
https://www.readbyqxmd.com/read/16123302/toll-like-receptor-8-mediated-reversal-of-cd4-regulatory-t-cell-function
#17
Guangyong Peng, Zhong Guo, Yukiko Kiniwa, Kui Shin Voo, Weiyi Peng, Tihui Fu, Daniel Y Wang, Yanchun Li, Helen Y Wang, Rong-Fu Wang
CD4+ regulatory T (Treg) cells have a profound ability to suppress host immune responses, yet little is understood about how these cells are regulated. We describe a mechanism linking Toll-like receptor (TLR) 8 signaling to the control of Treg cell function, in which synthetic and natural ligands for human TLR8 can reverse Treg cell function. This effect was independent of dendritic cells but required functional TLR8-MyD88-IRAK4 signaling in Treg cells. Adoptive transfer of TLR8 ligand-stimulated Treg cells into tumor-bearing mice enhanced anti-tumor immunity...
August 26, 2005: Science
https://www.readbyqxmd.com/read/15927069/high-throughput-kinase-assays-with-protein-substrates-using-fluorescent-polymer-superquenching
#18
Frauke Rininsland, Casey Stankewicz, Wendy Weatherford, Duncan McBranch
BACKGROUND: High-throughput screening is used by the pharmaceutical industry for identifying lead compounds that interact with targets of pharmacological interest. Because of the key role that aberrant regulation of protein phosphorylation plays in diseases such as cancer, diabetes and hypertension, kinases have become one of the main drug targets. With the exception of antibody-based assays, methods to screen for specific kinase activity are generally restricted to the use of small synthetic peptides as substrates...
2005: BMC Biotechnology
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