Christopher French
Joined 16 April 2009
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Caspase 8 is induced by tumor necrosis (TNF)-related apoptosis-inducing ligand (TRAIL). TRAIL induces apoptosis via death receptors (DR4 and DR5). After ligand binding the death receptor Fas recruits the adaptor protein FADD. FADD then binds and activates procaspase-8. Upon activation, Caspase 8 is then able activate caspase 3 and other downstream effectors. The end result is apoptosis (2,3). | Caspase 8 is induced by tumor necrosis (TNF)-related apoptosis-inducing ligand (TRAIL). TRAIL induces apoptosis via death receptors (DR4 and DR5). After ligand binding the death receptor Fas recruits the adaptor protein FADD. FADD then binds and activates procaspase-8. Upon activation, Caspase 8 is then able activate caspase 3 and other downstream effectors. The end result is apoptosis (2,3). | ||
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== Structure & Function== | == Structure & Function== | ||
{{STRUCTURE_1qtn | PDB=1qtn | SCENE= }} | |||
Caspase 8 is a 58 kilodalton protein that shares similarities with other members of the caspase family. The protein is composed of two subunits, referred to as <scene name='User:Christopher_French/Subunits/1'>p18 and p11</scene>. These two subunits form a heterodimer. The protein has a α/ß folding motif that has a <scene name='User:Christopher_French/B-sheets/1'>central six stranded beta sheet</scene>. Five of the strands are parallel and one is anti-parallel. The antiparallel strand is on the edge of the ß sheet. There are also six alpha helices in the protein structure. Three of these alpha helices are located on one side of the ß sheet and the other two on the other side, forming a <scene name='User:Christopher_French/Secondary_structure/3'>three layer sandwich</scene>. The p18 subunit has a Rossmann fold. There is a <scene name='User:Christopher_French/Turn_of_helix/2'>turn of helix</scene>(α1’) which is part of a large loop (loop 1). This is along the binding pocket region of the p18 subunit. There is a two-stranded antiparallel ß sheet found at the top of the main ß sheet which forms the base of the binding pocket (4,5). | |||
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Caspase-8 may be involved in various diseases including Huntington’s disease (HD), type two diabetes, autoimmune lymphoproliferative disease, arthritis, and cancer. HD is associated with increased HD gene product called huntingtin. Overexpression of this gene product induces apoptosis in cerebellar and striatal neurons. Patients with HD have increased activated caspase 8 in the affected regions of their brains. The mutated huntingtin does not bind huntingtin interacting protein-1 (Hip-1). Free Hip-1 which is in excess then binds and initiates the apoptotic cascade through capsase-8. Thus, modulation of the caspase-8 apoptotic cascade is an treatment strategy to patients with HD. Defects is caspase-8 may also be responsible for autoimmune lymphoproliferative syndrome (ALPS). Some ALPS patients have a <scene name='User:Christopher_French/Alps_mutation/1'>mutation</scene> in their caspase 8 gene that reduces protein stability and diminishes the enzymatic activity of the caspase 8 protein. Thus, caspase-8 plays a very important role in the immune system. Caspase 8 may play a role in arthritic diseases such as rheumatoid arthritis (RA). Deregulation of apoptosis in osteoblasts and T cells in rheumatoid synovium is a hallmark of RA. RA macrophages have reduced Fas-induced apoptosis. Caspase 8 may also play a role in cancer, where it acts as a tumor suppressor. Caspase-8 has been found to be downregulated in pediatric tumors and neuroendocrine lung tumors. Mutations in the caspase 8 gene have also been reported in small cell lung carcinoma. Downregulation of caspase 8 may lead to increased resistance to chemotherapy and increased metastasis. Thus, capase-8 upregulation and its inhibition are both attractive strategies for treatment in various diseases processes (6). | Caspase-8 may be involved in various diseases including Huntington’s disease (HD), type two diabetes, autoimmune lymphoproliferative disease, arthritis, and cancer. HD is associated with increased HD gene product called huntingtin. Overexpression of this gene product induces apoptosis in cerebellar and striatal neurons. Patients with HD have increased activated caspase 8 in the affected regions of their brains. The mutated huntingtin does not bind huntingtin interacting protein-1 (Hip-1). Free Hip-1 which is in excess then binds and initiates the apoptotic cascade through capsase-8. Thus, modulation of the caspase-8 apoptotic cascade is an treatment strategy to patients with HD. Defects is caspase-8 may also be responsible for autoimmune lymphoproliferative syndrome (ALPS). Some ALPS patients have a <scene name='User:Christopher_French/Alps_mutation/1'>mutation</scene> in their caspase 8 gene that reduces protein stability and diminishes the enzymatic activity of the caspase 8 protein. Thus, caspase-8 plays a very important role in the immune system. Caspase 8 may play a role in arthritic diseases such as rheumatoid arthritis (RA). Deregulation of apoptosis in osteoblasts and T cells in rheumatoid synovium is a hallmark of RA. RA macrophages have reduced Fas-induced apoptosis. Caspase 8 may also play a role in cancer, where it acts as a tumor suppressor. Caspase-8 has been found to be downregulated in pediatric tumors and neuroendocrine lung tumors. Mutations in the caspase 8 gene have also been reported in small cell lung carcinoma. Downregulation of caspase 8 may lead to increased resistance to chemotherapy and increased metastasis. Thus, capase-8 upregulation and its inhibition are both attractive strategies for treatment in various diseases processes (6). | ||