Receptor Activator of Nuclear Factor-kappa B
Receptors, Tumor Necrosis Factor
Receptors, Cytoplasmic and Nuclear
Bone and Bones
Fas Ligand Protein
Molecular Sequence Data
Amino Acid Sequence
TNF-Related Apoptosis-Inducing Ligand
Receptor activator of NF-kappaB recruits multiple TRAF family adaptors and activates c-Jun N-terminal kinase. (1/1553)Receptor activator of NF-kappaB (RANK) is a recently cloned member of the tumor necrosis factor receptor (TNFR) superfamily, and its function has been implicated in osteoclast differentiation and dendritic cell survival. Many of the TNFR family receptors recruit various members of the TNF receptor-associated factor (TRAF) family for transduction of their signals to NF-kappaB and c-Jun N-terminal kinase. In this study, the involvement of TRAF family members and the activation of the JNK pathway in signal transduction by RANK were investigated. TRAF1, 2, 3, 5, and 6 were found to bind RANK in vitro. Association of RANK with each of these TRAF proteins was also detected in vivo. Expression of RANK in cultured cells also induced the activation of JNK, which was blocked by a dominant-negative form of JNK. Furthermore, by employing various C-terminal deletion mutants of RANK, the regions responsible for TRAF interaction and JNK activation were identified. TRAF5 was determined to bind to the C-terminal 11 amino acids and the other TRAF members to a region N-terminal to the TRAF5 binding site. The domain responsible for JNK activation was localized to the same region where TRAF1, 2, 3, and 6 bound, which suggests that these TRAF molecules might mediate the RANK-induced JNK activation. (+info)
TRANCE, a TNF family member, is differentially expressed on T cell subsets and induces cytokine production in dendritic cells. (2/1553)TNF-related activation-induced cytokine (TRANCE) is a member of the TNF family recently identified in activated T cells. We report here that TRANCE mRNA is constitutively expressed in memory, but not naive, T cells and in single-positive thymocytes. Upon TCR/CD3 stimulation, TRANCE mRNA and surface protein expression are rapidly up-regulated in CD4+ and CD8+ T cells, which can be further enhanced on CD4+ T cells by CD28-mediated costimulation. However, TRANCE induction is significantly suppressed when cells are stimulated in the presence of IL-4, but is not modified in the presence of IFN-alpha, IFN-gamma, TGF-beta, TNF-alpha, or IL-2. High levels of TRANCE receptor expression are found on mature dendritic cells (DCs). In this study we show that activated T and B cells also express TRANCE receptor, but only at low levels. TRANCE, however, does not exert any significant effect on the proliferation, activation, or survival of those cells. In DCs, TRANCE induces the expression of proinflammatory cytokines (IL-6, IL-1) and T cell growth and differentiation factors (IL-12, IL-15) in addition to enhancing DC survival. Moreover, TRANCE cooperates with CD40 ligand or TNF-alpha to further increase the viability of DCs, suggesting that several TNF-related molecules on activated T cells may cooperatively regulate the function and survival of DCs to enhance T cell-mediated immune responses. (+info)
Activation of NF-kappaB by RANK requires tumor necrosis factor receptor-associated factor (TRAF) 6 and NF-kappaB-inducing kinase. Identification of a novel TRAF6 interaction motif. (3/1553)Various members of the tumor necrosis factor (TNF) receptor superfamily activate nuclear factor kappaB (NF-kappaB) and the c-Jun N-terminal kinase (JNK) pathways through their interaction with TNF receptor-associated factors (TRAFs) and NF-kappaB-inducing kinase (NIK). We have previously shown that the cytoplasmic domain of receptor activator of NF-kappaB (RANK) interacts with TRAF2, TRAF5, and TRAF6 and that its overexpression activates NF-kappaB and JNK pathways. Through a detailed mutational analysis of the cytoplasmic domain of RANK, we demonstrate that TRAF2 and TRAF5 bind to consensus TRAF binding motifs located in the C terminus at positions 565-568 and 606-611, respectively. In contrast, TRAF6 interacts with a novel motif located between residues 340 and 358 of RANK. Furthermore, transfection experiments with RANK and its deletion mutants in human embryonic 293 cells revealed that the TRAF6-binding region (340-358), but not the TRAF2 or TRAF5-binding region, is necessary and sufficient for RANK-induced NF-kappaB activation. Moreover, a kinase mutant of NIK (NIK-KM) inhibited RANK-induced NF-kappaB activation. However, RANK-mediated JNK activation required a distal portion (427-603) of RANK containing the TRAF2-binding domain. Thus, our results indicate that RANK interacts with various TRAFs through distinct motifs and activates NF-kappaB via a novel TRAF6 interaction motif, which then activates NIK, thus leading to NF-kappaB activation, whereas RANK most likely activates JNK through a TRAF2-interacting region in RANK. (+info)
Tumor necrosis factor receptor family member RANK mediates osteoclast differentiation and activation induced by osteoprotegerin ligand. (4/1553)A receptor that mediates osteoprotegerin ligand (OPGL)-induced osteoclast differentiation and activation has been identified via genomic analysis of a primary osteoclast precursor cell cDNA library and is identical to the tumor necrosis factor receptor (TNFR) family member RANK. The RANK mRNA was highly expressed by isolated bone marrow-derived osteoclast progenitors and by mature osteoclasts in vivo. Recombinant OPGL binds specifically to RANK expressed by transfected cell lines and purified osteoclast progenitors. Transgenic mice expressing a soluble RANK-Fc fusion protein have severe osteopetrosis because of a reduction in osteoclasts, similar to OPG transgenic mice. Recombinant RANK-Fc binds with high affinity to OPGL in vitro and blocks osteoclast differentiation and activation in vitro and in vivo. Furthermore, polyclonal Ab against the RANK extracellular domain promotes osteoclastogenesis in bone marrow cultures suggesting that RANK activation mediates the effects of OPGL on the osteoclast pathway. These data indicate that OPGL-induced osteoclastogenesis is directly mediated through RANK on osteoclast precursor cells. (+info)
TRANCE, a tumor necrosis factor family member critical for CD40 ligand-independent T helper cell activation. (5/1553)CD40 ligand (CD40L), a tumor necrosis factor (TNF) family member, plays a critical role in antigen-specific T cell responses in vivo. CD40L expressed on activated CD4(+) T cells stimulates antigen-presenting cells such as dendritic cells, resulting in the upregulation of costimulatory molecules and the production of various inflammatory cytokines required for CD4(+) T cell priming in vivo. However, CD40L- or CD40-deficient mice challenged with viruses mount protective CD4(+) T cell responses that produce normal levels of interferon gamma, suggesting a CD40L/CD40-independent mechanism of CD4(+) T cell priming that to date has not been elucidated. Here we show that CD4(+) T cell responses to viral infection were greatly diminished in CD40-deficient mice by administration of a soluble form of TNF-related activation-induced cytokine receptor (TRANCE-R) to inhibit the function of another TNF family member, TRANCE. Thus, the TRANCE/TRANCE-R interaction provides costimulation required for efficient CD4(+) T cell priming during viral infection in the absence of CD40L/CD40. These results also indicate that not even the potent inflammatory microenvironment induced by viral infections is sufficient to elicit efficient CD4(+) T cell priming without proper costimulation provided by the TNF family (CD40L or TRANCE). Moreover, the data suggest that TRANCE/TRANCE-R may be a novel and important target for immune intervention. (+info)
Promoter structure of mouse RANKL/TRANCE/OPGL/ODF gene. (6/1553)Receptor activator of NF-kappa B ligand (RANKL)/tumor necrosis factor-related activation induced cytokine (TRANCE)/osteoprotegerin ligand (OPGL)/osteoclast differentiation factor (ODF) is a membrane-bound signal transducer responsible for differentiation and maintenance of osteoclasts. To elucidate the mechanism regulating RANKL/TRANCE/OPGL/ODF gene expression, we cloned the 5'-flanking basic promoter region of the mouse RANKL/TRANCE/OPGL/ODF gene and characterized it by transient transfection studies and genomic Southern blot analysis. Inverted TATA- and CAAT-boxes and a putative Cbfa1/Osf2/AML3 binding domain constituted the basic promoter structure. The repeated half-sites for the vitamin D3 (VitD3) and glucocorticoid receptors were located at -935 and -640, respectively. Transient transfection studies revealed that short-term treatment with 1alpha,25(OH)2 VitD3 or dexamethasone increased luciferase activity up to 204% and 178%, respectively; on the other hand, treatment with dibutyryl cyclic AMP did not affect the promoter activity. Since the expression of Cbfa1/Osf2/AML3 is also regulated by VitD3, 1alpha,25(OH)2 VitD3 might affect RANKL/TRANCE/OPGL/ODF gene expression both directly and indirectly. CpG methylation was observed dominantly in mouse stromal cells, ST2, of a later passage which ceased to support in vitro osteoclastogenesis, suggesting that the methylation status of the CpG loci in the RANKL/TRANCE/OPGL/ODF gene promoter may be one of the influential cis-regulating factors. (+info)
Evidence for a role of a tumor necrosis factor-alpha (TNF-alpha)-converting enzyme-like protease in shedding of TRANCE, a TNF family member involved in osteoclastogenesis and dendritic cell survival. (7/1553)Tumor necrosis factor (TNF)-related activation-induced cytokine (TRANCE), a member of the TNF family, is a dendritic cell survival factor and is essential for osteoclastogenesis and osteoclast activation. In this report we demonstrate (i) that TRANCE, like TNF-alpha, is made as a membrane-anchored precursor, which is released from the plasma membrane by a metalloprotease; (ii) that soluble TRANCE has potent dendritic cell survival and osteoclastogenic activity; (iii) that the metalloprotease-disintegrin TNF-alpha convertase (TACE) can cleave immunoprecipitated TRANCE in vitro in a fashion that mimics the cleavage observed in tissue culture cells; and (iv) that in vitro cleavage of a TRANCE ectodomain/CD8 fusion protein and of a peptide corresponding to the TRANCE cleavage site by TACE occurs at the same site that is used when TRANCE is shed from cells into the supernatant. We propose that the TRANCE ectodomain is released from cells by TACE or a related metalloprotease-disintegrin, and that this release is an important component of the function of TRANCE in bone and immune homeostasis. (+info)
The ligand for osteoprotegerin (OPGL) directly activates mature osteoclasts. (8/1553)Osteoprotegerin (OPG) and OPG-ligand (OPGL) potently inhibit and stimulate, respectively, osteoclast differentiation (Simonet, W.S., D.L. Lacey, C.R. Dunstan, M. Kelley, M.-S. Chang, R. Luethy, H.Q. Nguyen, S. Wooden, L. Bennett, T. Boone, et al. 1997. Cell. 89:309-319; Lacey, D.L., E. Timms, H.-L. Tan, M.J. Kelley, C.R. Dunstan, T. Burgess, R. Elliott, A. Colombero, G. Elliott, S. Scully, et al. 1998. Cell. 93: 165-176), but their effects on mature osteoclasts are not well understood. Using primary cultures of rat osteoclasts on bone slices, we find that OPGL causes approximately sevenfold increase in total bone surface erosion. By scanning electron microscopy, OPGL-treated osteoclasts generate more clusters of lacunae on bone suggesting that multiple, spatially associated cycles of resorption have occurred. However, the size of individual resorption events are unchanged by OPGL treatment. Mechanistically, OPGL binds specifically to mature OCs and rapidly (within 30 min) induces actin ring formation; a marked cytoskeletal rearrangement that necessarily precedes bone resorption. Furthermore, we show that antibodies raised against the OPGL receptor, RANK, also induce actin ring formation. OPGL-treated mice exhibit increases in blood ionized Ca++ within 1 h after injections, consistent with immediate OC activation in vivo. Finally, we find that OPG blocks OPGL's effects on both actin ring formation and bone resorption. Together, these findings indicate that, in addition to their effects on OC precursors, OPGL and OPG have profound and direct effects on mature OCs and indicate that the OC receptor, RANK, mediates OPGL's effects. (+info)
In the medical field, RANK ligand, also known as osteoprotegerin ligand (OPGL), is a protein that plays a crucial role in bone remodeling and the regulation of bone homeostasis. It is a member of the tumor necrosis factor (TNF) superfamily of cytokines and is primarily produced by osteoblasts, which are cells responsible for bone formation. RANK ligand binds to a receptor called RANK (receptor activator of nuclear factor kappa-B) on the surface of osteoclasts, which are cells responsible for bone resorption or breakdown. The binding of RANK ligand to RANK triggers a signaling cascade that leads to the activation and differentiation of osteoclasts, promoting bone resorption. In addition to its role in bone remodeling, RANK ligand has been implicated in various other physiological and pathological processes, including inflammation, cancer, and autoimmune diseases. Therefore, targeting RANK ligand has become an attractive therapeutic strategy for the treatment of these conditions.
Receptor Activator of Nuclear Factor-kappa B (RANK) is a protein that plays a critical role in the regulation of bone remodeling and the development of osteoclasts, which are cells responsible for breaking down bone tissue. RANK is expressed on the surface of osteoclast precursors and is activated by binding to its ligand, RANKL (Receptor Activator of Nuclear Factor-kappa B Ligand), which is produced by osteoblasts and other cells in the bone microenvironment. Activation of RANK by RANKL leads to the recruitment and activation of the transcription factor NF-kappaB, which promotes the differentiation and survival of osteoclasts. Dysregulation of RANK/RANKL signaling has been implicated in a number of bone disorders, including osteoporosis, osteopetrosis, and rheumatoid arthritis.
Osteoprotegerin (OPG) is a protein that plays a critical role in bone metabolism and is involved in the regulation of bone resorption, or the breakdown of bone tissue. It is produced by osteoblasts, which are cells responsible for bone formation, and by other cells in the body, including immune cells and endothelial cells. OPG acts as a decoy receptor for the receptor activator of nuclear factor kappa-B ligand (RANKL), a protein that stimulates osteoclasts, the cells responsible for bone resorption. By binding to RANKL, OPG prevents it from binding to its target receptor on osteoclasts, thereby inhibiting osteoclast activation and bone resorption. In the medical field, OPG has been studied for its potential role in the treatment of osteoporosis, a condition characterized by low bone density and an increased risk of fractures. OPG has also been studied in the context of other bone-related disorders, such as Paget's disease of bone and multiple myeloma, as well as in the regulation of bone metabolism in other organs, such as the kidneys and the lungs.
Receptors, Tumor Necrosis Factor (TNF receptors) are proteins found on the surface of cells that bind to the cytokine tumor necrosis factor (TNF). TNF is a signaling molecule that plays a role in the immune response and inflammation. There are two main types of TNF receptors: TNFR1 (also known as TNFRp55) and TNFR2 (also known as TNFRp75). TNFR1 is expressed on most cell types and is involved in the regulation of cell survival, proliferation, and apoptosis (programmed cell death). TNFR2 is primarily expressed on immune cells and is involved in immune cell activation and differentiation. TNF receptors can be activated by binding to TNF, which triggers a signaling cascade within the cell. This signaling cascade can lead to a variety of cellular responses, including the activation of immune cells, the induction of inflammation, and the promotion of cell survival or death. Abnormalities in TNF receptor signaling have been implicated in a number of diseases, including autoimmune disorders, inflammatory diseases, and certain types of cancer. As a result, TNF receptors are the targets of several drugs used to treat these conditions, including TNF inhibitors.
Osteitis deformans, also known as Paget's disease of bone, is a chronic disorder of the skeletal system characterized by increased bone turnover and abnormal bone remodeling. It typically affects older adults and is more common in men than women. The disease is characterized by periods of increased bone resorption (breakdown) and formation (rebuilding), leading to thickening and weakening of the bone. This can cause bone pain, deformities, and an increased risk of fractures. The exact cause of osteitis deformans is not fully understood, but it is thought to be related to genetic and environmental factors. Treatment typically involves medications to slow down bone turnover and relieve symptoms, as well as physical therapy to maintain bone strength and prevent fractures.
Receptors, Cytoplasmic and Nuclear are proteins that are found within the cytoplasm and nucleus of cells. These receptors are responsible for binding to specific molecules, such as hormones or neurotransmitters, and triggering a response within the cell. This response can include changes in gene expression, enzyme activity, or other cellular processes. In the medical field, understanding the function and regulation of these receptors is important for understanding how cells respond to various stimuli and for developing treatments for a wide range of diseases.
Membrane glycoproteins are proteins that are attached to the cell membrane through a glycosyl group, which is a complex carbohydrate. These proteins play important roles in cell signaling, cell adhesion, and cell recognition. They are involved in a wide range of biological processes, including immune response, cell growth and differentiation, and nerve transmission. Membrane glycoproteins can be classified into two main types: transmembrane glycoproteins, which span the entire cell membrane, and peripheral glycoproteins, which are located on one side of the membrane.
Bone resorption is a process in which bone tissue is broken down and removed by osteoclasts, which are specialized cells in the bone marrow. This process is a normal part of bone remodeling, which is the continuous process of bone formation and resorption that occurs throughout life. Bone resorption is necessary for the growth and development of bones, as well as for the repair of damaged bone tissue. However, excessive bone resorption can lead to a number of medical conditions, including osteoporosis, which is a condition characterized by weak and brittle bones that are prone to fractures. Other conditions that can be caused by excessive bone resorption include Paget's disease of bone, which is a disorder that causes the bones to become abnormally thick and weak, and hyperparathyroidism, which is a condition in which the parathyroid glands produce too much parathyroid hormone, which can lead to increased bone resorption. Bone resorption can also be caused by certain medications, such as corticosteroids, and by certain medical conditions, such as cancer and rheumatoid arthritis. In these cases, bone resorption can lead to a loss of bone mass and density, which can increase the risk of fractures and other complications.
Osteolysis is a medical condition characterized by the breakdown and destruction of bone tissue. It can occur in various parts of the body, including the bones of the spine, pelvis, and extremities. Osteolysis can be caused by a variety of factors, including infection, inflammation, trauma, and certain medical conditions such as osteoporosis, cancer, and metabolic disorders. It can also be a complication of certain medical treatments, such as chemotherapy or radiation therapy. The symptoms of osteolysis may include pain, swelling, and tenderness in the affected area, as well as weakness or instability in the affected joint. In severe cases, osteolysis can lead to the formation of bone cysts or tumors, which can cause further complications. Treatment for osteolysis depends on the underlying cause and the severity of the condition. In some cases, medications may be used to manage pain and inflammation, while in other cases, surgery may be necessary to remove damaged bone tissue or stabilize the affected joint. In some cases, physical therapy or other forms of rehabilitation may also be recommended to help improve strength and mobility.
In the medical field, carrier proteins are proteins that transport molecules across cell membranes or within cells. These proteins bind to specific molecules, such as hormones, nutrients, or waste products, and facilitate their movement across the membrane or within the cell. Carrier proteins play a crucial role in maintaining the proper balance of molecules within cells and between cells. They are involved in a wide range of physiological processes, including nutrient absorption, hormone regulation, and waste elimination. There are several types of carrier proteins, including facilitated diffusion carriers, active transport carriers, and ion channels. Each type of carrier protein has a specific function and mechanism of action. Understanding the role of carrier proteins in the body is important for diagnosing and treating various medical conditions, such as genetic disorders, metabolic disorders, and neurological disorders.
Glycoproteins are a type of protein that contains one or more carbohydrate chains covalently attached to the protein molecule. These carbohydrate chains are made up of sugars and are often referred to as glycans. Glycoproteins play important roles in many biological processes, including cell signaling, cell adhesion, and immune response. They are found in many different types of cells and tissues throughout the body, and are often used as markers for various diseases and conditions. In the medical field, glycoproteins are often studied as potential targets for the development of new drugs and therapies.
Osteoporosis is a medical condition characterized by a decrease in bone density and strength, making bones more fragile and prone to fractures. It is a common condition, particularly in older adults, and can affect both men and women. In osteoporosis, the bones become porous and brittle, which can lead to fractures even with minor trauma or falls. The most common sites for osteoporosis-related fractures are the spine, hip, and wrist. Osteoporosis is often diagnosed through a bone density test, which measures the amount of bone mineral density in the hip and spine. Risk factors for osteoporosis include age, gender, family history, smoking, excessive alcohol consumption, and certain medical conditions such as thyroid disease or rheumatoid arthritis. Treatment for osteoporosis typically involves medications to increase bone density and reduce the risk of fractures, as well as lifestyle changes such as regular exercise and a healthy diet rich in calcium and vitamin D.
Bone neoplasms are abnormal growths or tumors that develop in the bones. They can be either benign (non-cancerous) or malignant (cancerous). Benign bone neoplasms are usually slow-growing and do not spread to other parts of the body, while malignant bone neoplasms can be invasive and spread to other parts of the body through the bloodstream or lymphatic system. There are several types of bone neoplasms, including osteosarcoma, Ewing's sarcoma, chondrosarcoma, and multiple myeloma. These tumors can affect any bone in the body, but they are most commonly found in the long bones of the arms and legs, such as the femur and tibia. Symptoms of bone neoplasms may include pain, swelling, and tenderness in the affected bone, as well as bone fractures that do not heal properly. Diagnosis typically involves imaging tests such as X-rays, MRI scans, and CT scans, as well as a biopsy to examine a sample of the tumor tissue. Treatment for bone neoplasms depends on the type and stage of the tumor, as well as the patient's overall health. Options may include surgery to remove the tumor, radiation therapy to kill cancer cells, chemotherapy to shrink the tumor, and targeted therapy to block the growth of cancer cells. In some cases, a combination of these treatments may be used.
In the medical field, "bone and bones" typically refers to the skeletal system, which is made up of bones, cartilage, ligaments, tendons, and other connective tissues. The skeletal system provides support and structure to the body, protects vital organs, and allows for movement through the use of muscles. Bones are the main component of the skeletal system and are responsible for providing support and protection to the body. There are 206 bones in the human body, which are classified into four types: long bones, short bones, flat bones, and irregular bones. Long bones, such as the femur and humerus, are cylindrical in shape and are found in the arms and legs. Short bones, such as the carpals and tarsals, are cube-shaped and are found in the wrists and ankles. Flat bones, such as the skull and ribs, are thin and flat and provide protection to vital organs. Irregular bones, such as the vertebrae and pelvis, have complex shapes that allow for specific functions. Overall, the bone and bones of the skeletal system play a crucial role in maintaining the health and function of the human body.
CD40 Ligand (CD40L) is a protein that is expressed on the surface of activated T cells, B cells, and dendritic cells. It plays a critical role in the immune response by binding to the CD40 receptor on the surface of antigen-presenting cells (APCs), such as dendritic cells and B cells. This interaction triggers a signaling cascade that leads to the activation and proliferation of APCs, as well as the differentiation of T cells into effector cells that can attack infected cells or cancer cells. CD40L is also involved in the regulation of inflammation and the development of autoimmunity. In the medical field, CD40L is being studied as a potential target for the treatment of various diseases, including cancer, autoimmune disorders, and infectious diseases.
Cell differentiation is the process by which cells acquire specialized functions and characteristics during development. It is a fundamental process that occurs in all multicellular organisms, allowing cells to differentiate into various types of cells with specific functions, such as muscle cells, nerve cells, and blood cells. During cell differentiation, cells undergo changes in their shape, size, and function, as well as changes in the proteins and other molecules they produce. These changes are controlled by a complex network of genes and signaling pathways that regulate the expression of specific genes in different cell types. Cell differentiation is a critical process for the proper development and function of tissues and organs in the body. It is also involved in tissue repair and regeneration, as well as in the progression of diseases such as cancer, where cells lose their normal differentiation and become cancerous.
Fas Ligand Protein (FasL) is a type of protein that plays a crucial role in the regulation of the immune system. It is also known as tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) or Apo-2L. FasL is expressed on the surface of certain immune cells, such as natural killer (NK) cells and cytotoxic T cells, and it binds to a protein receptor called Fas (also known as CD95) on the surface of target cells. When FasL binds to Fas, it triggers a process called apoptosis, which is a form of programmed cell death. In the context of the immune system, FasL is important for eliminating infected or cancerous cells. However, when FasL is expressed at high levels, it can also contribute to autoimmune diseases and tissue damage. Therefore, the regulation of FasL expression is tightly controlled in the body.
In the medical field, "Cells, Cultured" refers to cells that have been grown and maintained in a controlled environment outside of their natural biological context, typically in a laboratory setting. This process is known as cell culture and involves the isolation of cells from a tissue or organism, followed by their growth and proliferation in a nutrient-rich medium. Cultured cells can be derived from a variety of sources, including human or animal tissues, and can be used for a wide range of applications in medicine and research. For example, cultured cells can be used to study the behavior and function of specific cell types, to develop new drugs and therapies, and to test the safety and efficacy of medical products. Cultured cells can be grown in various types of containers, such as flasks or Petri dishes, and can be maintained at different temperatures and humidity levels to optimize their growth and survival. The medium used to culture cells typically contains a combination of nutrients, growth factors, and other substances that support cell growth and proliferation. Overall, the use of cultured cells has revolutionized medical research and has led to many important discoveries and advancements in the field of medicine.
In the medical field, binding sites refer to specific locations on the surface of a protein molecule where a ligand (a molecule that binds to the protein) can attach. These binding sites are often formed by a specific arrangement of amino acids within the protein, and they are critical for the protein's function. Binding sites can be found on a wide range of proteins, including enzymes, receptors, and transporters. When a ligand binds to a protein's binding site, it can cause a conformational change in the protein, which can alter its activity or function. For example, a hormone may bind to a receptor protein, triggering a signaling cascade that leads to a specific cellular response. Understanding the structure and function of binding sites is important in many areas of medicine, including drug discovery and development, as well as the study of diseases caused by mutations in proteins that affect their binding sites. By targeting specific binding sites on proteins, researchers can develop drugs that modulate protein activity and potentially treat a wide range of diseases.
In the medical field, an amino acid sequence refers to the linear order of amino acids in a protein molecule. Proteins are made up of chains of amino acids, and the specific sequence of these amino acids determines the protein's structure and function. The amino acid sequence is determined by the genetic code, which is a set of rules that specifies how the sequence of nucleotides in DNA is translated into the sequence of amino acids in a protein. Each amino acid is represented by a three-letter code, and the sequence of these codes is the amino acid sequence of the protein. The amino acid sequence is important because it determines the protein's three-dimensional structure, which in turn determines its function. Small changes in the amino acid sequence can have significant effects on the protein's structure and function, and this can lead to diseases or disorders. For example, mutations in the amino acid sequence of a protein involved in blood clotting can lead to bleeding disorders.
TNF-Related Apoptosis-Inducing Ligand (TRAIL) is a protein that plays a role in the regulation of programmed cell death, also known as apoptosis. It is a member of the tumor necrosis factor (TNF) superfamily of cytokines and is expressed by a variety of cells, including immune cells and some cancer cells. TRAIL binds to specific receptors on the surface of target cells, triggering a cascade of events that ultimately leads to the activation of caspases, a family of proteases that play a central role in the execution of apoptosis. TRAIL-induced apoptosis is a highly selective process, as it primarily targets cells that express the TRAIL receptors, while sparing normal cells. TRAIL has been studied as a potential therapeutic agent for the treatment of various types of cancer, as many cancer cells are highly sensitive to TRAIL-induced apoptosis. However, some cancer cells have developed resistance to TRAIL, which has limited its clinical utility. Despite this, ongoing research is exploring ways to overcome TRAIL resistance and enhance its anti-cancer effects.
CD30 ligand, also known as CD153 or tumor necrosis factor superfamily member 8 (TNFSF8), is a protein that plays a role in the immune system. It is expressed on the surface of activated T cells, B cells, and some types of cancer cells. CD30 ligand binds to a protein called CD30, which is found on the surface of activated T cells and some types of cancer cells. This interaction can stimulate the growth and survival of CD30-expressing cells, and it has been implicated in the development and progression of certain types of cancer, such as Hodgkin's lymphoma and anaplastic large cell lymphoma. CD30 ligand is also being studied as a potential target for cancer therapy.
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- As we previously reported, receptor activator of nuclear factor kappa-B (RANK) ligand (RANKL)/RANK signaling on M2 macrophages promotes the production of chemokines and proinflammatory cytokines to maintain the immunosuppressive tumor environment of extramammary Paget's disease (EMPD). (iiarjournals.org)
- Since EMPD is a skin adenocarcinoma of apocrine gland origin that expresses high levels of RANKL and matrix metalloproteinase (MMP) 7, and EMPD is associated with the presence of RANK + M2 macrophages, we hypothesized that tumor-associated macrophages (TAMs) in adenocarcinomas such as PCAC might also express RANKL and MMP7. (iiarjournals.org)
- Conclusion: Our study suggests that the RANKL/RANK pathway contributes to the development and maintenance of the immunosuppressive tumor microenvironment and denosumab may be a promising adjuvant therapy targeting TAMs in cancer of apocrine origin. (iiarjournals.org)
- RANK binds to transmembrane protein nuclear factor-κB receptor activating factor ligand (RANKL) to activate RANK/RANKL, TRAF6/RANKL/MAPKs, TRAF6/ RANKL/NF-κB, Wnt/RANKL/RANKL, and JAK2/STAT3/RANKL. (frontiersin.org)
- Osteoprotegerin is one of two receptor proteins that can attach (bind) to a protein called receptor activator of NF-κB ligand (RANKL). (medlineplus.gov)
- Because RANKL can only bind to one receptor at a time, osteoprotegerin and RANK compete with one another. (medlineplus.gov)
- When RANKL is bound to RANK, it sets off a series of chemical signals that trigger immature osteoclasts to mature and become fully functional. (medlineplus.gov)
- By reducing the amount of RANKL that is available to bind to RANK, osteoprotegerin plays a critical role in regulating the process of bone remodeling. (medlineplus.gov)
- Without osteoprotegerin, RANKL binds only to RANK. (medlineplus.gov)
- 20. Lossdorfer S, Gotz W, Jager A. Immunohistochemical localization of receptor activator of nuclear factor kappaB (RANK) and its ligand (RANKL) in human deciduous teeth. (bvsalud.org)
- The ability to rank covalent molecular binders with similar warheads using SILCS ligand grid free energy (LGFE) ranking was also tested for several proteins. (nih.gov)
- To facilitate the design of this class of ligands, computational methods can be used to help identify reactive nucleophilic residues, frequently cysteines, on a target protein for covalent binding, to test various warhead groups for their potential reactivities, and to predict noncovalent contributions to binding that can facilitate drug-target interactions that are important for binding specificity. (nih.gov)
- Developing new computational methods for ligand discovery and 2. (ucsf.edu)
- Developing computational methods to relate receptors by the similarity of their ligands, rather than by protein sequence or structure. (ucsf.edu)
- This gene encodes a member of the tumor necrosis factor (TNF) cytokine family which is a ligand for osteoprotegerin and functions as a key factor for osteoclast differentiation and activation. (arigobio.com)
- Many of the signaling pathways that control normal bone homeostasis are at play in pathologic PCa bone metastases, including the receptor activator of nuclear factor-kB/receptor activator of nuclear factor-kB ligand/osteoprotegerin system. (mssm.edu)
- and Prolia is a RANK ligand inhibitor. (mainlinetoday.com)
Receptor activator of nuclear factor3
- Prolia works by blocking a protein called RANK (receptor activator of nuclear factor kappa beta) and helps prevent bone cells called osteoclasts from breaking down bone in the body. (medlineplus.gov)
- For example, Paget's cells release soluble receptor activator of nuclear factor kappa-B ligand (sRANKL) into the tumor microenvironment, stimulating RANK + TAMs to produce CCL17, which recruits Tregs into the lesional skin of patients with extramammary Paget's disease (EMPD) ( 11 , 17 ). (iiarjournals.org)
- Its differentiation and function are mainly regulated by macrophage colony-stimulating factor (M- CSF), receptor activator of nuclear factor kappa B(RANK) ( 7 ). (frontiersin.org)
- Immunohistochemical staining of MMP1 and MMP25 as well as chemokine (C-C motif) ligand (CCL) 5 in the lesional skin from five patients with PCAC showed a substantial number of MMP1-bearing cells and MMP25-bearing cells, as well as CCL5-producing cells, that were distributed in the lesional skin. (iiarjournals.org)
- Ligands in a complex dictate the reactivity of the central atom, including ligand substitution rates, the reactivity of the ligands themselves, and redox. (wikipedia.org)
- Binding of the metal with the ligands results in a set of molecular orbitals, where the metal can be identified with a new HOMO and LUMO (the orbitals defining the properties and reactivity of the resulting complex) and a certain ordering of the 5 d-orbitals (which may be filled, or partially filled with electrons). (wikipedia.org)
- Denosumab is a fully human monoclonal antibody that targets RANK Ligand (an essential mediator of cells that break down bone) and is being investigated for its potential to treat and prevent a broad range of bone loss conditions including osteoporosis and bone metastases. (amgen.com)
- Denosumab is a fully human monoclonal antibody that targets RANK Ligand and is being investigated for its potential to prevent and treat a broad range of bone loss conditions including osteoporosis, bone metastases, treatment-induced bone loss, multiple myeloma and bone erosions in rheumatoid arthritis. (amgen.com)
- Denosumab is the first late-stage investigational therapy that specifically inhibits RANK Ligand, an essential mediator of the cells that break down bone. (amgen.com)
- Flare Free Energy Perturbation (FEP) offers a quantitative method to reliably calculate relative binding affinity, enabling accurate ranking of molecules in a congeneric ligand series. (cresset-group.com)
- The ligand with the better scoring is more likely to have a better affinity and therefore more likely to bind which is the premise for any pharmacological effect at the target. (biosolveit.de)
- It assesses the binding affinity of any ligand in a binding site, be it from docking or from a crystal structure. (biosolveit.de)
- The size of the sphere reflects the quantitive contribution to the overall binding affinity of the ligand. (biosolveit.de)
- RÉSUMÉ L'objectif de l'étude était d'évaler l'importance clinique du ligand de CD40 soluble (sCD40L) chez des patients atteints d'un carcinome hépatocellulaire (CHC) associé au virus de l'hépatite C (VHC). (who.int)
- The nature of metal-ligand bonding can range from covalent to ionic. (wikipedia.org)
- To further aid covalent drug design, we extended a functional group mapping approach based on explicit solvent all-atom molecular simulations (SILCS: site identification by ligand competitive saturation) that intrinsically considers protein flexibility, functional group, and protein desolvation along with functional group-protein interactions. (nih.gov)
- In coordination chemistry, a ligand is an ion or molecule with a functional group that binds to a central metal atom to form a coordination complex. (wikipedia.org)
- This means that Flare users can make better, accurately informed decisions around which ligand modifications can achieve the best results, with new molecule designs often ending up quite far away from the initial starting point. (cresset-group.com)
- ARG81958 Rat sRANK Ligand / TNFSF11 / TRANCE ELISA Kit is an Enzyme Immunoassay kit for the quantification of Rat sRANK Ligand / TNFSF11 / TRANCE in serum, plasma (heparin, EDTA) and cell culture supernatants. (arigobio.com)
- This changes pharmacological relationships dramatically-targets that would normally be considered sequence neighbors are pushed far apart (because their ligands are dissimilar), whereas other targets that supposedly have nothing to do with one another become neighbors (because their ligands are very similar). (ucsf.edu)
- Measurements of the free energy change associated with axial ligand exchange in a cationic europium tetraamide complex, [Eu(DOTAMPh)](CF3SO3)3 supported by a simple electrostatic perturbation model, have been interpreted in terms of a predominant donor atom polarisation model which affords a simple assessment of Ln ion donor atom preference and ranks the axial second-order ligand field coefficient. (open.ac.uk)
- For the purposes of ranking ligands, however, the properties of the octahedral complexes and the resulting Δo has been of primary interest. (wikipedia.org)
- The arrangement of the d-orbitals on the central atom (as determined by the 'strength' of the ligand), has a strong effect on virtually all the properties of the resulting complexes. (wikipedia.org)
- This parameter has been measured directly, by analysing the europium emission spectra for a series of eight- and nine-coordinate axially symmetric complexes based on cyclen including aza-carboxylate ligands (e.g. (open.ac.uk)
- Metals and metalloids are bound to ligands in almost all circumstances, although gaseous "naked" metal ions can be generated in a high vacuum. (wikipedia.org)
- Ligands are classified in many ways, including: charge, size (bulk), the identity of the coordinating atom(s), and the number of electrons donated to the metal (denticity or hapticity). (wikipedia.org)
- According to the molecular orbital theory, the HOMO (Highest Occupied Molecular Orbital) of the ligand should have an energy that overlaps with the LUMO (Lowest Unoccupied Molecular Orbital) of the metal preferential. (wikipedia.org)
- Les concentrations sériques de sCD40L circulant et d'interleukine 10 circulante ont été analysées à l'aide de la méthode immuno-enzymatique chez 30 patients positifs pour le VHC avec un CHC, chez 30 patients patients positifs pour le VHC avec une cirrhose du foie, et chez 30 volontaires d'âge correspondant en bonne santé avec des anticorps anti-VHC négatifs servant de groupe témoin. (who.int)
- Subtle differences are detected between two forms of FepA, ligand-free and complexed with its natural iron carrier, the enterobactin. (nature.com)
- First is to design a fully automated platform for structure-based ligand virtual screening featuring an information theory-based compound selection. (hhs.gov)
- This work led to the discovery of RANK-positive progenitors as a target for breast cancer prevention in BRCA1 mutation carriers. (edu.au)
- Benchmarking experiments can be used to gain confidence that your system is prepared correctly, confirming the predictivity of the method on the target and ligand series of interest. (cresset-group.com)
- Scoring assesses the interaction quality of the complex (ligand and target) of a pose. (biosolveit.de)
- The magnitude of Δo is determined by the field-strength of the ligand: strong field ligands, by definition, increase Δo more than weak field ligands. (wikipedia.org)
- one ranking system focuses on ligand 'hardness' (see also hard/soft acid/base theory). (wikipedia.org)
- Ligand selection requires critical consideration in many practical areas, including bioinorganic and medicinal chemistry, homogeneous catalysis, and environmental chemistry. (wikipedia.org)
- A longstanding effort to do so is by exploiting protein structures to predict new reagents and therapeutic leads (structure-based ligand discovery). (ucsf.edu)
- By using the Maximum Entropy Method, we will be able to enhance the specificity of scoring functions for ligand ranking. (hhs.gov)
- ARG81958 Rat RANK Ligand / TNFSF11 / TRANCE ELISA Kit results of a typical standard run with optical density reading at 450 nm. (arigobio.com)
- You can see the complete list of today's Zacks #1 Rank (Strong Buy) stocks here . (yahoo.com)
- This ordering of ligands is almost invariable for all metal ions and is called spectrochemical series. (wikipedia.org)
- FEP projects can begin with a much smaller number of ligands than may be required for other methods. (cresset-group.com)
- Furthermore, the metal-ligand bond order can range from one to three. (wikipedia.org)
- He showed, among other things, that the formulas of many cobalt(III) and chromium(III) compounds can be understood if the metal has six ligands in an octahedral geometry. (wikipedia.org)
- Metal ions preferentially bind certain ligands. (wikipedia.org)
- Statistical analyses were performed using nonparametric Mann-Whitney rank sum test. (cdc.gov)