Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.B4 (granzyme K)
 43 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Gene expression profiling may improve the understanding of the biology behind relapse in pediatric acute lymphoblastic leukemia. Using suppression subtractive hybridization (SSH), cDNA concatenated sequencing (CCS), and reverse transcriptase real-time quantitative polymerase chain reaction (RT-RQ-PCR) on high-risk patient samples with nondeterminant chromosomal translocation, the authors identified 3 genes that were significantly overexpressed in the nonrelapsed patients: the calcium/calmodulin-dependent serine protein kinase (CASK), subunit 2 of the cofactor required for SP1 transcriptional activation (CRSP2), and granzyme K (GZMK). The level of expression of these biomarkers may help identify patients with potentially good prognosis within a group otherwise at high risk of relapse.
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PMID:Identification of prognosis markers in pediatric high-risk acute lymphoblastic leukemia. 1616 56

Granzymes are serine proteases released from the granules of cytotoxic lymphocytes during the induction of apoptosis. To evaluate the physiologic role of human granzyme K (GzmK), we developed a sensitive ELISA which was shown to specifically detect human GzmK in its active as well as its inactive conformation. Analysis of the lysate of lymphokine-activated killer (LAK) cells by gel filtration revealed that GzmK seems to be complexed to proteoglycans within these cells. While the expression of GzmA and B by cytotoxic lymphocytes was strongly up-regulated in response to several activating stimuli, GzmK expression did not increase significantly above constitutive levels, indicating differential regulation of these granzymes. However, low levels of GzmK were detected in plasma samples of healthy volunteers, which were in the same range as levels of GzmA and B. Furthermore, circulating levels of GzmK as well as of GzmA and B were significantly elevated in patients suffering from viral infections. We conclude that GzmK protein is produced by cytotoxic cells, and just as GzmA and B it can be released in a soluble form into the extracellular space. Furthermore, our data suggest that despite a more restricted cellular expression pattern, GzmK seems to participate in immune responses against several viruses.
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PMID:Detection of soluble human granzyme K in vitro and in vivo. 1620 62

We employed human SK-MEL-28 cells as a model system to identify cellular proteins that accompany N-(4-methyl)phenyl-O-(4-methoxy)phenyl-thionocarbamate (MMTC)-induced apoptosis based on a proteomic approach. Cell viability tests revealed that SK-MEL-28 skin cancer cells underwent more cell death than normal HaCaT cells in a dose-dependent manner after treatment with MMTC. Two-dimensional electrophoresis in conjunction with matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF) mass spectrometry analysis or computer matching with a protein database further revealed that the MMTC-induced apoptosis is accompanied by increased levels of caspase-1, checkpoint suppressor-1, caspase-4, NF-kappaB inhibitor, AP-2, c-Jun-N-terminal kinase, melanoma inhibitor, granzyme K, G1/S specific cyclin D3, cystein rich protein, Ras-related protein Rab-37 or Ras-related protein Rab-13, and reduced levels of EMS (oncogene), ATP synthase, tyrosine-phosphatase, Cdc25c, 14-3-3 protein or specific structure of nuclear receptor. The migration suppressing effect of MMTC on SK-MEL-28 cell was tested. MMTC suppressed the metastasis of SK-MEL-8 cells. It was also identified that MMTC had little angiogenic effect because it did not suppress the proliferation of HUVEC cell line. These results suggest that MMTC is a novel chemotherapeutic and metastatic agents against the SK-MEL-28 human melanoma cell line.
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PMID:Proteomic analysis and the antimetastatic effect of N-(4-methyl)phenyl-O-(4-methoxy) phenyl-thionocarbamate-induced apoptosis in human melanoma SK-MEL-28 cells. 1659 96

Granule-mediated cytolysis is the major pathway for killer lymphocytes to kill pathogens and tumor cells. Little is known about how granzyme K functions in killer lymphocyte-mediated cytolysis. We previously showed that human GzmK triggers rapid cell death independently of caspase activation with single-stranded DNA nicks, similar to GzmA. In this study we found that GzmK can induce rapid reactive oxygen species generation and collapse of mitochondrial inner membrane potential (DeltaPsim). Blockade of reactive oxygen species production by antioxidant N-acetylcysteine or superoxide scavenger Tiron inhibits GzmK-induced cell death. Moreover GzmK targets mitochondria by cleaving Bid to generate its active form tBid, which disrupts the outer mitochondrial membrane leading to the release of cytochrome c and endonuclease G. Thus, we showed herein that GzmK-induced caspase-independent death occurs through Bid-dependent mitochondrial damage that is different from GzmA.
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PMID:Granzyme K directly processes bid to release cytochrome c and endonuclease G leading to mitochondria-dependent cell death. 1730 7

Granzyme K (Gzm K) and granzyme A (GzmA) are the only two tryptases among all the granzymes. Tryptase activity is necessary for cytotoxic T lymphocyte (CTL)/nature killer (NK) cells-mediated cytolysis. Granzyme K might be a potent granzyme to rescue the activity of granzyme A. Granzyme K expresses at high levels in CD56(high) NK cells, memory CD8+ T cells and CD56+ T cells. We recently demonstrated human granzyme K induces rapid cell death with rapid externalization of phosphatidylserine, nuclear morphological changes and single-stranded DNA nicks. Moreover, Granzyme K can induce rapid reactive oxygen species (ROS) generation and collapse of mitochondrial inner membrane potential. Blockade of reactive oxygen species accumulation suppresses granzyme K-induced cell death. However, it is unknown about how reactive oxygen species generate in Granzyme K-mediated apoptosis. Here we found the redox factor-1/apurinic apyrimidinic endonuclease Ape1 can antagonize reactive oxygen species generation. Overexpression of Ape1 inhibits, whereas silencing Ape1 expression potentiates reactive oxygen species accumulation under treatment with oxidative reagents or loading with granzyme K. Ape1 is a physiological substrate of granzyme K. Ape1 cleavage by granzyme K facilitates intracellular reactive oxygen species accumulation and enhances granzyme K-induced cell death.
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PMID:Granzyme K degrades the redox/DNA repair enzyme Ape1 to trigger oxidative stress of target cells leading to cytotoxicity. 1817 23

Tumor regressions have been observed in a small proportion of melanoma patients vaccinated with a MAGE-A3 peptide presented by HLA-A1, administered as peptide, ALVAC canarypox virus containing a MAGE-A3 minigene, or peptide-pulsed dendritic cells (DC). There was a correlation between tumor regression and the detection of anti-MAGE-3.A1 CTL responses. These responses were monoclonal and often of a very low magnitude after vaccination with peptide or ALVAC, and usually polyclonal and of a higher magnitude after DC vaccination. These results suggested that, at least in some patients, surprisingly few anti-MAGE-3.A1 T-cells could initiate a tumor regression process. To understand the role of these T cells, we carried out a functional analysis of anti-MAGE-3.A1 CTL clones derived from vaccinated patients who displayed tumor regression. The functional avidities of these CTL clones, evaluated in lysis assays, were surprisingly low, suggesting that high avidity was not part of the putative capability of these CTL to trigger tumor rejection. Most anti-MAGE-3.A1 CTL clones obtained after DC vaccination, but not after peptide or ALVAC vaccination, produced interleukin 10. Transcript profiling confirmed these results and indicated that approximately 20 genes, including CD40L, prostaglandin D2 synthase, granzyme K, and granzyme H, were highly differentially expressed between the anti-MAGE-3.A1 CTL clones derived from patients vaccinated with either peptide-ALVAC or peptide-pulsed DC. These results indicate that the modality of vaccination with a tumor-specific antigen influences the differentiation pathway of the antivaccine CD8 T-cells, which may have an effect on their capacity to trigger a tumor rejection response.
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PMID:Functions of Anti-MAGE T-cells induced in melanoma patients under different vaccination modalities. 1848 79

Cytotoxic CD8 T cells exert their antiviral and antitumor activity primarily through the secretion of cytotoxic granules. Degranulation activity and cytotoxic granules (perforin plus granzymes) generally define CD8 T cells with cytotoxic function. In this study, we have investigated the expression of granzyme K (GrmK) in comparison to that of GrmA, GrmB, and perforin. The expression of the cytotoxic granules was assessed in virus-specific CD8 T cells specific to influenza virus, Epstein-Barr virus (EBV), cytomegalovirus (CMV), or human immunodeficiency virus type 1 (HIV-1). We observed a dichotomy between GrmK and perforin expression in virus-specific CD8 T cells. The profile in influenza virus-specific CD8 T cells was perforin(-) GrmB(-) GrmA(+/-) GrmK(+); in CMV-specific cells, it was perforin(+) GrmB(+) GrmA(+) GrmK(-/+); and in EBV- and HIV-1-specific cells, it was perforin(-/+) GrmB(+) GrmA(+) GrmK(+). On the basis of the delineation of memory and effector CD8 T cells with CD45RA and CD127, the GrmK(+) profile was associated with early-stage memory CD8 T-cell differentiation, the perforin(+) GrmB(+) GrmA(+) profile with advanced-stage differentiation, and the GrmB(+) GrmA(+) Grmk(+) profile with intermediate-stage differentiation. Furthermore, perforin and GrmB but not GrmA and GrmK correlated with cytotoxic activity. Finally, changes in antigen exposure in vitro and in vivo during primary HIV-1 infection and vaccination modulated cytotoxic granule profiles. These results advance our understanding of the relationship between distinct profiles of cytotoxic granules in memory CD8 T cells and function, differentiation stage, and antigen exposure.
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PMID:Distinct profiles of cytotoxic granules in memory CD8 T cells correlate with function, differentiation stage, and antigen exposure. 1917 26

Inactivation of tumor suppressor p53 results in loss of the apoptosis-regulating function of the p53 protein in tumor cells. Restoration of wild-type p53 expression in p53 mutant tumor cells increases tumor susceptibility to CTL-mediated cytolysis. However, the direct role of p53 in regulating tumor sensitivity to NK cell-mediated lysis and the functional relationship between p53 and granzymes in the control of tumor killing are still poorly documented. In this study, we found that p53 can sensitize tumor-killing susceptibility to NK and granzyme K-mediated cytolysis. Granzyme K is constitutively expressed in high levels in NK cells and induces rapid caspase-independent cell death. Granzyme K may exert a critical role in NK cell-mediated tumor clearance. p53 associates with granzyme K and is a physiological substrate of granzyme K. p53 was processed to three cleavage products of p40, p35, and p13 fragments at Lys(24) and Lys(305). These three cleavage products harbor strong proapoptotic activities that amplify the proapoptotic action of p53 to potentiate tumor-killing sensitivity. Therefore, p53 is as a cytotoxic bomb that can be triggered by granzyme K, leading to potentiating killing efficacy.
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PMID:Ignition of p53 bomb sensitizes tumor cells to granzyme K-mediated cytolysis. 1920 68

Functional NK cell deficiencies are associated with autoimmune diseases, including multiple sclerosis. NK cells can promote or inhibit adaptive immunity via either cytokine production or cytotoxicity toward immature dendritic cells and activated T cells. In humans, this immunoregulatory role resides in the CD56(bright) NK cell subset, which is selectively expanded by daclizumab, a CD25-blocking Ab that suppresses multiple sclerosis-associated inflammation. The objective of this study was to investigate the molecular mechanisms underlying the cytotoxicity of NK cells toward activated T cells. We demonstrated that NK cells induce caspase-independent apoptosis that requires NK cell degranulation and causes mitochondrial dysfunction in activated T cells. Although both granzyme A and granzyme K (GrK) can mediate this form of apoptosis, quantitatively we observed preferential transfer of GrK to target cells. Consequently, gene silencing of GrK in the NK-92 cell line, which retains functional characteristics of CD56(bright) NK cells, profoundly inhibited the ability of NK-92 cells to kill activated syngeneic T cells. Finally, we demonstrated that daclizumab treatment significantly enhanced this newly defined mechanism of cytotoxicity by CD56(bright) NK cells. Our study describes the important physiological role that GrK plays in immunoregulation of adaptive immunity in humans and indicates that therapeutic exploitation of this pathway is beneficial in controlling autoimmunity.
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PMID:Unexpected role for granzyme K in CD56bright NK cell-mediated immunoregulation of multiple sclerosis. 2166 61

Pathogenic yeast and fungi represent a major group of human pathogens. The consequences of infections are diverse and range from local, clinically uncomplicated mycosis of the skin to systemic, life-threatening sepsis. Despite extensive MHC class I-restricted frequencies of yeast-specific CD8 T lymphocytes in healthy individuals and the essential role of the cell-mediated immunity in controlling infections, the characteristics and defense mechanisms of antifungal effector cells are still unclear. Here, we describe the direct analysis of yeast-specific CD8 T lymphocytes in whole blood from healthy individuals. They show a unique, nonclassical phenotype expressing granulysin and granzyme K in lytic granules instead of the major effector molecules perforin and granzyme B. After stimulation in whole blood, yeast-specific CD8 T cells degranulated and, upon cultivation in the presence of IL-2, their granula were refilled with granulysin rather than with perforin and granzyme B. Moreover, yeast-specific stimulation through dendritic cells but not by yeast cells alone led to degranulation of the effector cells. As granulysin is the only effector molecule in lytic granules known to have antifungal properties, our data suggest yeast-specific CD8 T cells to be a nonclassical effector population whose antimicrobial effector machinery seems to be tailor-made for the efficient elimination of fungi as pathogens.
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PMID:Human yeast-specific CD8 T lymphocytes show a nonclassical effector molecule profile. 2194 67


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