CTPS1 is a novel therapeutic target in multiple myeloma which synergizes with inhibition of CHEK1, ATR or WEE1.

Targeting nucleotide biosynthesis is a proven strategy for the treatment of cancer but is limited by toxicity, reflecting the fundamental nucleotide requirement of dividing cells. The rate limiting step in de novo pyrimidine synthesis is of interest, being catalyzed by two homologous enzymes, CTP synthase 1 (CTPS1) and CTPS2, that could be differentially targeted. Herein, analyses of publicly available datasets identified an essential role for CTPS1 in multiple myeloma (MM), linking high expression of CTPS1 (but not CTPS2) with advanced disease and poor outcomes.

CTP Synthase 1 Is a Novel Therapeutic Target in Lymphoma.

Lymphoma is the most common hematological malignancy and is among the 10 most prevalent cancers worldwide. Although survival has been improved by modern immunochemotherapeutic regimens, there remains a significant need for novel targeted agents to treat both B-cell and T-cell malignancies. Cytidine triphosphate synthase 1 (CTPS1), which catalyzes the rate-limiting step in pyrimidine synthesis, plays an essential and nonredundant role in B-cell and T-cell proliferation but is complemented by the homologous CTPS2 isoform outside the hemopoietic system.

Low density lipoprotein receptor-related protein 1 (LRP1)-mediated endocytic clearance of a disintegrin and metalloproteinase with thrombospondin motifs-4 (ADAMTS-4): functional differences of non-catalytic domains of ADAMTS-4 and ADAMTS-5 in LRP1 binding.

Degradation of the cartilage proteoglycan aggrecan is an early event in the development of osteoarthritis, and a disintegrin and metalloproteinase with thrombospondin motifs-4 (ADAMTS-4) and ADAMTS-5 are considered to be the major aggrecan-degrading enzymes. We have recently found that ADAMTS-5 is rapidly endocytosed via low density lipoprotein receptor-related protein 1 (LRP1) and degraded by chondrocytes. Here we report that this regulatory mechanism also applies to ADAMTS-4, although its rate of endocytosis is slower than that of ADAMTS-5.

STAT3-driven upregulation of TLR2 promotes gastric tumorigenesis independent of tumor inflammation.

Gastric cancer (GC) is associated with chronic inflammation; however, the molecular mechanisms promoting tumorigenesis remain ill defined. Using a GC mouse model driven by hyperactivation of the signal transducer and activator of transcription (STAT)3 oncogene, we show that STAT3 directly upregulates the epithelial expression of the inflammatory mediator Toll-like receptor (TLR)2 in gastric tumors. Genetic and therapeutic targeting of TLR2 inhibited gastric tumorigenesis, but not inflammation, characterized by reduced proliferation and increased apoptosis of the gastric epithelium.

Toll-like receptors as targets for immune disorders.

Since the identification of the first Toll-like receptor (TLR) in humans in 1997, understanding of the molecular basis for innate immunity has increased significantly. The TLR family and downstream signalling pathways have been extensively characterised, There is now significant evidence suggesting a role for TLRs in human inflammatory and immune diseases such as rheumatoid arthritis, diabetes, allergy/asthma and atherosclerosis. Various approaches have been taken to identify novel therapeutic agents targeting TLRs including biologics, small molecules and nucleic acid-based drugs.

Matrix metalloproteinase 17 is necessary for cartilage aggrecan degradation in an inflammatory environment.

Objective: Aggrecan is a critical component of cartilage extracellular matrix. Several members of the 'a disintegrin and metalloproteinase with thrombospondin motifs' (ADAMTS) family have been characterised as aggrecanases by their ability to generate fragments containing the NITEGE neoepitope from aggrecan. Increased NITEGE fragments in synovial fluid and articular cartilage are a hallmark of osteoarthritis (OA) and it is hypothesised that the enhanced rate of aggrecan degradation is critical for cartilage destruction in OA.

Targeting Toll-like receptors: emerging therapeutics?

There is a growing interest in the targeting of Toll-like receptors (TLRs) for the prevention and treatment of cancer, rheumatoid arthritis, inflammatory bowel disease and systemic lupus erythematosus (SLE). Several new compounds are now undergoing preclinical and clinical evaluation, with a particular focus on TLR7 and TLR9 activators as adjuvants in infection and cancer, and inhibitors of TLR2, TLR4, TLR7 and TLR9 for the treatment of sepsis and inflammatory diseases. Here, we focus on TLRs that hold the most promise for drug discovery research, highlighting agents that are in the discovery phase and in clinical trials,and on the emerging new aspects of TLR-mediated signalling - such as control by ubiquitination and regulation by microRNAs - that might offer further possibilities of therapeutic manipulation.

MMP28 gene expression is regulated by Sp1 transcription factor acetylation.

MMP-28 (epilysin) is a recently cloned member of the MMP (matrix metalloproteinase) family. It is highly expressed in the skin by keratinocytes, the developing and regenerating nervous system and a number of other normal human tissues, as well as a number of carcinomas. The MMP28 promoter has previously been cloned and characterized identifying a conserved GT-box that binds Sp1/Sp3 (specificity proteins 1 and 3) proteins and is essential for the basal expression of the gene.

Toll-like receptors and NOD-like receptors in rheumatic diseases.

The past 10 years have seen the description of families of receptors that drive proinflammatory cytokine production in infection and tissue injury. Two major classes have been examined in the context of inflammatory joint disease--the Toll-like receptors (TLRs) and NOD-like receptors (NLRs). TLRs such as TLR2 and TLR4 are being implicated in the pathology of rheumatoid arthritis, ankylosing spondylitis, lyme arthritis and osteoarthritis.

Characterization and regulation of ADAMTS-16.

The ADAMTS (a disintegrin and metalloproteinase domain with thrombospondin motifs) family includes 19 secreted proteinases in man. ADAMTS16 is a recently cloned gene expressed at high levels in fetal lung and kidney and adult brain and ovary. The ADAMTS-16 protein currently has no known function.

Expression and function of matrix metalloproteinase (MMP)-28.

Matrix metalloproteinase-28 (MMP-28, epilysin) is highly expressed in the skin by keratinocytes, the developing and regenerating nervous system and a number of other normal human tissues. In epithelial cells, over-expression of MMP-28 mediates irreversible epithelial to mesenchymal transition concomitant with loss of E-cadherin from the cell surface and an increase in active transforming growth factor beta. We recently reported the expression of MMP-28 in both cartilage and synovium where expression is increased in patients with osteoarthritis.

Localization of the cis-enhancer element for mouse type X collagen expression in hypertrophic chondrocytes in vivo.

The type X collagen gene (Col10a1) is a specific molecular marker of hypertrophic chondrocytes during endochondral bone formation. Mutations in human COL10A1 and altered chondrocyte hypertrophy have been associated with multiple skeletal disorders. However, until recently, the cis-enhancer element that specifies Col10a1 expression in hypertrophic chondrocytes in vivo has remained unidentified.

Crystal structures of human ADAMTS-1 reveal a conserved catalytic domain and a disintegrin-like domain with a fold homologous to cysteine-rich domains.

The ADAMTS (a disintegrin-like and metalloproteinase domain with thrombospondin type I motifs) family of proteases plays a role in pathological conditions including arthritis, cancer, thrombotic thrombocytopenic purpura and the Ehlers-Danlos type VIIC and Weill-Marchesani genetic syndromes. Here, we report the first crystal structures for a member of the ADAMTS family, ADAMTS-1. Originally cloned as an inflammation-associated gene, ADAMTS-1 has been shown to be involved in tissue remodelling, wound healing and angiogenesis.

Nurr1 dependent regulation of pro-inflammatory mediators in immortalised synovial fibroblasts.

Background: Nurr1 is an orphan member of the nuclear receptor superfamily; these orphan receptors are a group for which a ligand has yet to be identified. Nurr1 has been shown to regulate the expression of a small number of genes as a monomeric, constitutively active receptor. These Nurr1 regulated genes are primarily associated with dopamine cell maturation and survival.

Expression profiling of metalloproteinases and their inhibitors in cartilage.

Objective: To profile the expression of all known members of the matrix metalloproteinase (MMP), ADAMTS, and tissue inhibitor of metalloproteinases (TIMP) gene families in normal cartilage and cartilage from patients with osteoarthritis (OA).

Methods: Human cartilage was obtained from femoral heads at joint replacement for OA or following fracture to the femoral neck. Total RNA was purified, and gene expression was assayed using quantitative real-time polymerase chain reaction.

Metalloproteinases: their role in arthritis and potential as therapeutic targets.

Irreversible degradation of articular cartilage is a major feature of the arthritides, and its prevention is a therapeutic goal which has been difficult to achieve. Enzymes from the matrix metalloproteinase and ADAMTS (a disintegrin, a metalloproteinase, and thrombospondin motif) families are key mediators of cartilage extracellular matrix destruction. Inhibition of metalloproteinase activity is therefore a conceptually attractive therapeutic strategy, although clinical efficacy has not yet been demonstrated.