FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2076609293> ?p ?o ?g. }

• W2076609293 endingPage "566" @default.
• W2076609293 startingPage "565" @default.
• W2076609293 abstract "Granzymes are a family of structurally related serine proteases that differ markedly in their substrate specificities. Although these proteases were predicted to function as intracellular and/or extracellular proteases in processes ranging from cell death to extracellular matrix cleavage to viral inactivation, intense research over the past two decades has focused primarily on their contributions as intracellular proteolytic mediators of cell death. This can be attributed at least in part to landmark studies by Hayes et al. demonstrating a synergistic cytotoxic effect when cells were exposed to perforin/cytolysin and granzymes. Since then, and perhaps fostered by the exponential growth of apoptosis research funding in the 1990s, there have been relatively fewer investigations into the potential broader functionality of these proteases with respect to non-apoptotic and/or perforinindependent functions. There are 5 human granzymes (A, B, H, K, M) and 11 mouse granzymes (A, B, C, D, E, F, G, K, L, M, N). One potential explanation for such diversity is to ensure efficient immune-mediated killing of unwanted cells that could otherwise be resistant to the proteolytic activity of a single granzyme. To examine a pan-granzyme role in immunity and disease, perforin knockout mice were, and still are, often used to indirectly determine whether granzymes exert a causative role in disease. If perforin-deficient mice did not elicit a differential response or outcome, it was, and still is, often concluded that the granule pathway is not involved. However, based on emerging evidence, one must question whether using perforin knockout mice exclusively to evaluate a role for granzymes in disease is appropriate. In this issue of Cell Death and Differentiation, a number of articles are provided that summarize the role of granzymes and perforin in a variety of pathologies and present data arguing for both perforin-dependent and perforin-independent functions of these enzymes in cytotoxicity and other responses. Clearly, one cannot ignore the extensive literature pertaining to the granzyme B/perforin pathway in immune-mediated apoptosis. Indeed, as discussed by Brennan et al., a complete loss of cytotoxic lymphocyte perforin function results in familial haemophagocytic lymphohistiocytosis, while a partial loss of perforin function appears to strongly predispose patients to haematological malignancies. However, although perforin knockout mice are susceptible to tumorigenesis, the same cannot be said for single granzyme knockout mice, suggesting that it is necessary to prevent the internalization of multiple granzymes and/or other factors to attenuate tumour clearance. Alternatively, it is possible that perforin may possess certain, as yet undefined, granzyme-independent effects on cells. The granzyme B/perforin pathway has been proposed as the predominant mechanism for immune-mediated apoptosis of allogeneic cells. As such, this pathway is important in acute and chronic organ transplant rejection. As discussed by Choy, while findings using perforin or granzyme B knockout mice are mixed for acute rejection due to differences in transplantation models, both molecules appear to be important for T cell-mediated destruction of allogeneic cells and grafts, and both appear to be important in chronic rejection as their absence results in reduced allograft vasculopathy in mouse models of heart transplant rejection. As with most ailments, a role for other granzymes in acute or chronic rejection remains unknown. Another interesting, potentially perforin-dependent role for granzymes is emerging in diabetes research. As discussed by Thomas et al. in this issue, perforin deficiency attenuates type I diabetes by reducing islet/beta cell death, suggesting that this pathway is important, while recent evidence presents a role for granzyme-mediated inflammation in this disease. As further support for the granule pathway in disease, mutations in perforin are associated with type I diabetes. As a redundant role for other pro-apoptotic inducers such as FasL has been proposed, it will be important to determine if and how autoantigen production and/or pro-inflammatory cytokine production contribute to diabetes. An area that remains poorly understood is the role of endogenous granzyme inhibitors in the physiological regulation of granzyme activity and in pathogenesis. As discussed in the review by Kaiserman and Bird, although inhibitors have been identified for some granzymes, surprisingly little is known pertaining to any pathophysiological role for granzyme serine protease inhibitors (serpins) in disease. Much research needs to be done to verify whether they inhibit granzymes in vivo and whether alterations in their regulation, levels, and/or activity are altered in disease. Further, identification and characterization of granzyme serpins have focused primarily on intracellular inhibitors of apoptosis. Owing to" @default.
• W2076609293 created "2016-06-24" @default.
• W2076609293 creator A5018173253 @default.
• W2076609293 date "2010-03-15" @default.
• W2076609293 modified "2023-10-07" @default.
• W2076609293 title "Granzymes in disease: bench to bedside" @default.
• W2076609293 cites W1495097924 @default.
• W2076609293 cites W1591446606 @default.
• W2076609293 cites W1976019359 @default.
• W2076609293 cites W1992776047 @default.
• W2076609293 cites W1994236426 @default.
• W2076609293 cites W2005981959 @default.
• W2076609293 cites W2012110635 @default.
• W2076609293 cites W2012267998 @default.
• W2076609293 cites W2041673031 @default.
• W2076609293 cites W2042527150 @default.
• W2076609293 cites W2061576158 @default.
• W2076609293 cites W2066236445 @default.
• W2076609293 cites W2076474632 @default.
• W2076609293 cites W2077855603 @default.
• W2076609293 cites W2084542841 @default.
• W2076609293 cites W2129080097 @default.
• W2076609293 doi "https://doi.org/10.1038/cdd.2009.218" @default.
• W2076609293 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/20228822" @default.
• W2076609293 hasPublicationYear "2010" @default.
• W2076609293 type Work @default.
• W2076609293 sameAs 2076609293 @default.
• W2076609293 citedByCount "36" @default.
• W2076609293 countsByYear W20766092932012 @default.
• W2076609293 countsByYear W20766092932013 @default.
• W2076609293 countsByYear W20766092932014 @default.
• W2076609293 countsByYear W20766092932015 @default.
• W2076609293 countsByYear W20766092932016 @default.
• W2076609293 countsByYear W20766092932017 @default.
• W2076609293 countsByYear W20766092932018 @default.
• W2076609293 countsByYear W20766092932019 @default.
• W2076609293 countsByYear W20766092932020 @default.
• W2076609293 countsByYear W20766092932021 @default.
• W2076609293 countsByYear W20766092932022 @default.
• W2076609293 countsByYear W20766092932023 @default.
• W2076609293 crossrefType "journal-article" @default.
• W2076609293 hasAuthorship W2076609293A5018173253 @default.
• W2076609293 hasBestOaLocation W20766092931 @default.
• W2076609293 hasConcept C142724271 @default.
• W2076609293 hasConcept C167672396 @default.
• W2076609293 hasConcept C183193105 @default.
• W2076609293 hasConcept C19527891 @default.
• W2076609293 hasConcept C203014093 @default.
• W2076609293 hasConcept C2776062744 @default.
• W2076609293 hasConcept C2779134260 @default.
• W2076609293 hasConcept C3020000666 @default.
• W2076609293 hasConcept C70721500 @default.
• W2076609293 hasConcept C71924100 @default.
• W2076609293 hasConcept C86803240 @default.
• W2076609293 hasConcept C8891405 @default.
• W2076609293 hasConceptScore W2076609293C142724271 @default.
• W2076609293 hasConceptScore W2076609293C167672396 @default.
• W2076609293 hasConceptScore W2076609293C183193105 @default.
• W2076609293 hasConceptScore W2076609293C19527891 @default.
• W2076609293 hasConceptScore W2076609293C203014093 @default.
• W2076609293 hasConceptScore W2076609293C2776062744 @default.
• W2076609293 hasConceptScore W2076609293C2779134260 @default.
• W2076609293 hasConceptScore W2076609293C3020000666 @default.
• W2076609293 hasConceptScore W2076609293C70721500 @default.
• W2076609293 hasConceptScore W2076609293C71924100 @default.
• W2076609293 hasConceptScore W2076609293C86803240 @default.
• W2076609293 hasConceptScore W2076609293C8891405 @default.
• W2076609293 hasIssue "4" @default.
• W2076609293 hasLocation W20766092931 @default.
• W2076609293 hasLocation W20766092932 @default.
• W2076609293 hasOpenAccess W2076609293 @default.
• W2076609293 hasPrimaryLocation W20766092931 @default.
• W2076609293 hasRelatedWork W2062533676 @default.
• W2076609293 hasRelatedWork W2077261484 @default.
• W2076609293 hasRelatedWork W2082482010 @default.
• W2076609293 hasRelatedWork W2126619650 @default.
• W2076609293 hasRelatedWork W2147794249 @default.
• W2076609293 hasRelatedWork W2463737032 @default.
• W2076609293 hasRelatedWork W2553645446 @default.
• W2076609293 hasRelatedWork W2914225367 @default.
• W2076609293 hasRelatedWork W2949557421 @default.
• W2076609293 hasRelatedWork W801791243 @default.
• W2076609293 hasVolume "17" @default.
• W2076609293 isParatext "false" @default.
• W2076609293 isRetracted "false" @default.
• W2076609293 magId "2076609293" @default.
• W2076609293 workType "article" @default.