Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.1 (protein kinase)
 81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent studies have identified protein kinase Cθ (PKCtheta), a member of the Ca(2+)-independent PKC family, as an essential component of the T-cell synapse that cooperates with calcineurin to activate the interleukin-2 (IL-2) gene. Several selective functions of PKCtheta involved in the activation and survival of T cells are reviewed herein. Among these, the nuclear factor-kappaB (NF-kappaB) signaling cascade appears to be the most critical target of PKCtheta in the T-cell receptor/CD28 costimulatory pathway that leads to T-cell activation.
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PMID:Protein kinase Ctheta: a new essential superstar on the T-cell stage. 1109 61

Cdk9 is the catalytic subunit of TAK (cyclinT1/P-TEFb), a cellular protein kinase that mediates human immunodeficiency virus type 1 (HIV-1) Tat transcriptional activation function. To examine Cdk9 function in cells relevant to HIV-1 infection, we used a murine leukemia virus retrovirus vector to transduce and overexpress the cDNA of a dominant negative mutant Cdk9 protein (Cdk9-dn) in Jurkat T cells and U937 promonocytic cells. In Jurkat cells, overexpression of Cdk9-dn specifically inhibited Tat transactivation and HIV-1 replication but had no inhibitory effect on induction of CD69, CD25, and interleukin-2 following T-cell activation. In U937 cells, overexpression of Cdk9-dn sensitized cells to apoptosis, especially after phorbol myristate acetate (PMA) treatment to induce differentiation to macrophage-like cells. Because Cdk9 function is induced in PMA-treated U937 cells, Cdk9 may play an antiapoptotic role during monocyte differentiation.
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PMID:Antiapoptotic function of Cdk9 (TAK/P-TEFb) in U937 promonocytic cells. 1115 95

Receptors for many neurotransmitters including catecholamines and acetylcholine (ACh) have been detected on the cell surface of lymphocytes. It has been demonstrated that a human T cell line synthesizes ACh and suggested that ACh may be an autacoid modulating T cell-dependent immune responses. However, the biochemical interactions of the ACh system with the immune system have not been elucidated in detail. We have shown that m1 and m2 muscarinic receptor mRNAs are expressed in human peripheral blood lymphocytes and in human T cell line Jurkat cells and that pretreatment of these cells with a muscarinic receptor agonist enhances interleukin-2 (IL-2) production. We also postulated possible intracellular signaling pathways via which muscarinic receptors regulate IL-2 production in Jurkat cells. The findings suggest that M1 muscarinic receptors are involved in muscarinic receptor-mediated enhancement of IL-2 production in Jurkat cells and that the transcription factor AP-1 and pathways via mitogen-activated protein kinase (MAPK)/extracellular signal regulated protein kinase and c-Jun N-terminal kinase, but not via p38 MAPK, may be involved in the muscarinic receptor-mediated enhancement of IL-2 production. Our findings demonstrate a neuro-immune interaction through muscarinic receptor signaling in immune cells.
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PMID:Roles of muscarinic acetylcholine receptors in interleukin-2 synthesis in lymphocytes. 1124 67

Cannabinoid compounds inhibit the cAMP signalling cascade in leukocytes. One of these compounds, cannabinol (CBN) has been shown to inhibit interleukin-2 (IL-2) expression and the activation of cAMP response element binding protein (CREB) and nuclear factor for immunoglobulin kappa chain in B cells (NF-kappaB) following phorbol-12-myristate-13 acetate (PMA) plus ionomycin (Io) treatment of thymocytes. Therefore, the objective of the present studies was to determine the role of cAMP and protein kinase A (PKA) in the CBN-mediated inhibition of IL-2, CREB, and NF-kappaB in PMA/Io-activated thymocytes. The inhibition of CREB/ATF-1 phosphorylation, or cAMP response element (CRE) or kappaB DNA binding activity produced by CBN in PMA/Io-activated thymocytes, could not be reversed by DBcAMP costimulation. Furthermore, DBcAMP failed to reverse the concentration-dependent inhibition of IL-2 protein secretion by CBN. Pretreatment of thymocytes with H89 produced a modest inhibition of PMA/Io-induced CREB/ATF-1 phosphorylation and CRE DNA binding activity but H89 had no effect on protein binding to a kappaB motif. Additionally, H89 modestly inhibited PMA/Io-induced IL-2 secretion. In light of the modest involvement of the cAMP pathway in CBN-mediated inhibition of CREB and IL-2 in PMA/Io-activated thymocytes, PD098059 (PD), the MEK inhibitor, was utilized to determine the role of ERK MAP kinases in thymocytes. ERKs play a critical role in IL-2 production but not for CREB phsophorylation. Collectively, these findings suggest that CBN may modulate several signalling pathways in activated T cells.
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PMID:Modulation of CREB and NF-kappaB signal transduction by cannabinol in activated thymocytes. 1130 41

A human protein kinase, p53-related protein kinase (PRPK), was cloned from an interleukin-2-activated cytotoxic T-cell subtraction library. PRPK appears to be a homologue of a growth-related yeast serine/threonine protein kinase, YGR262c. However, a complementation assay using YGR262c-disrupted yeast indicated that PRPK is not functionally identical to the yeast enzyme. PRPK expression was observed in interleukin-2-activated cytotoxic T-cells, some human epithelial tumor cell lines, and the testes. The intrinsic transcriptional activity of p53 was up-regulated by a transient transfection of PRPK to COS-7 cells. PRPK was shown to bind to p53 and to phosphorylate p53 at Ser-15. These results indicate that PRPK may play an important role in the cell cycle and cell apoptosis through phosphorylation of p53.
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PMID:Cloning and characterization of a p53-related protein kinase expressed in interleukin-2-activated cytotoxic T-cells, epithelial tumor cell lines, and the testes. 1154 6

The immunosuppressive effect of rapamycin is mediated by inhibition of interleukin-2-stimulated T cell proliferation. We report for the first time that rapamycin also inhibits growth factor-induced proliferation of cultured mouse proximal tubular (MPT; IC(50) ~1 ng/ml) cells and promotes apoptosis of these cells by impairing the survival effects of the same growth factors. On the basis of these in vitro data, we tested the hypothesis that rapamycin would impair recovery of renal function after ischemic acute renal failure induced in vivo by renal artery occlusion (RAO). Rats given daily injections of rapamycin or vehicle were subjected to RAO or sham surgery. Rapamycin had no effect on the glomerular filtration rate (GFR) of sham-operated animals. In rats subjected to RAO, GFR fell to comparable levels 1 day later in vehicle- and rapamycin-treated rats (0.25 +/- 0.08 and 0.12 +/- 0.05 ml. min(-1). 300 g(-1), respectively) (P = not significant). In vehicle-treated rats subjected to RAO, GFR increased to 0.61 +/- 0.08 ml. min(-1). 300 g(-1) on day 3 (P < 0.02 vs. day 1) and then rose further to 0.99 +/- 0.09 ml. min(-1). 300 g(-1) on day 4 (P < 0.02 vs. day 3). By contrast, GFR did not improve in rapamycin-treated rats subjected to RAO over the same time period. Rapamycin also increased apoptosis of tubular cells while markedly reducing their proliferative response after RAO. Furthermore, rapamycin inhibited activation of 70-kDa S6 protein kinase (p70(S6k)) in cultured MPT cells as well as in the renal tissue of rats subjected to RAO. We conclude that rapamycin severely impairs the recovery of renal function after ischemia-reperfusion injury. This effect appears to be due to the combined effects of increased tubular cell loss (via apoptosis) and profound inhibition of the regenerative response of tubular cells. These effects are likely mediated by inhibition of p70(S6k).
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PMID:Rapamycin impairs recovery from acute renal failure: role of cell-cycle arrest and apoptosis of tubular cells. 1155 17

In addition to macromolecular interactions that provide co-stimulation during antigen-presenting cell (APC) and CD4+ T-cell conjugation, covalent chemical events between specialized ligands have been implicated in T-cell co-stimulation. These take the form of transient Schiff base formation between carbonyls and amines expressed on APC and T-cell surfaces. Small Schiff base-forming molecules, such as tucaresol, can substitute for the physiological donor of carbonyl groups and provide co-stimulation to T cells, thereby functioning as orally active immunopotentiatory drugs. The Schiff base co-stimulatory pathway in T cells has been partially characterized in terms of changes in Na+ and K+ transport, and activation of the mitogen activated protein kinase (MAPK) ERK2. In the present study, the effects of Schiff base co-stimulation by tucaresol on the T-cell receptor (TCR)-dependent pathway leading to Ca2+ release were investigated. Schiff base co-stimulation by tucaresol was found to prime for enhanced TCR-dependent phospholipase C-gamma phosphorylation, inositol 1,4,5-triphosphate production, and Ca2+ mobilization that correlated with functional enhancement of interleukin-2 production in primary T cells. The effects on Ca2+ occurred comparably in Jurkat and primary CD4+ T cells responding to anti-CD3 monoclonal antibody. Enhancement of the Ca2+ response required a 10-min priming period and was prevented by prior covalent ligation of cell-surface free amino groups by sulpho-N-hydroxy succinimido-biotin; clofilium-mediated inhibition of tucaresol-induced changes in intracellular K+; and selective inhibition of the MAPK pathway. The data are consistent with a priming mechanism in which late co-stimulation-triggered events exert a positive influence on early TCR-triggered events. In additional studies of murine T cells expressing trans-gene TCRs, tucaresol was likewise shown to prime for enhanced Ca2+ mobilization in response to physiological TCR-engagement by MHC-peptide complexes.
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PMID:Schiff base-mediated co-stimulation primes the T-cell-receptor-dependent calcium signalling pathway in CD4 T cells. 1157 20

Combinations of cytokines are known to reactivate transcription and replication of latent human immunodeficiency virus type 1 (HIV-1) proviruses in resting CD4(+) T lymphocytes isolated from infected individuals. Transcription of the HIV-1 provirus by RNA polymerase II is strongly stimulated by the viral Tat protein. Tat function is mediated by a cellular protein kinase known as TAK (cyclin T1/P-TEFb) that is composed of Cdk9 and cyclin T1. We have found that treatment of peripheral blood lymphocytes and purified resting CD4(+) T lymphocytes with the combination of interleukin-2 (IL-2), IL-6, and tumor necrosis factor alpha resulted in an increase in Cdk9 and cyclin T1 protein levels and an increase in TAK enzymatic activity. The cytokine induction of TAK in resting CD4(+) T lymphocytes did not appear to require proliferation of lymphocytes. These results suggest that induction of TAK by cytokines secreted in the microenvironment of lymphoid tissue may be involved in the reactivation of HIV-1 in CD4(+) T lymphocytes harboring a latent provirus.
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PMID:Induction of TAK (cyclin T1/P-TEFb) in purified resting CD4(+) T lymphocytes by combination of cytokines. 1168 14

We have previously reported on a defect in both extracellular signal-regulated protein kinase (ERK) and c-jun N-terminal kinase (JNK) mitogen-activated protein kinase (MAPK) activation in splenocytes obtained from old rats. In order to investigate whether these effects are conserved across species, we have now used mouse splenocytes to measure the effect of aging on the activation of the same two MAPK families: ERK and JNK. Our results demonstrate that, as in rats, both MAPK signal transduction pathways are affected by aging in mice, indicating the existence of a further defect located downstream of the receptor-proximal events. Whereas ERK1 and p46(JNK) activation were not significantly modified, the kinetics of both ERK2 and p54(JNK) activation and inactivation were affected in splenocytes from old animals. Specifically, by analyzing the kinetics of activation and inactivation of these enzymes, we found a nearly 50% decrease in the fold of activation of both ERK2 and p54(JNK). These defects result in an overall diminution of enzyme activities without changes in the steady-state levels of relevant proteins. The impaired activity of these two MAPK pathways is likely to play a role in the reduced expression of interleukin-2 and diminished lymphoproliferation observed in old animals.
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PMID:Defect in ERK2 and p54(JNK) activation in aging mouse splenocytes. 1181 22

The aim of the present study was to investigate whether interleukin-2 (IL-2) is involved in the proliferation control of the cultured RC-4B/C cell, which is a derived pituitary adenoma cell line of the rat. The level of cell proliferation was estimated by assessing (3)H-thymidine ((3)H-TdR) incorporation rate. IL-2 (10 1000 U/ml) significantly stimulated (3)H-TdR incorporation into the cell line in a dose-dependent manner. Specific PTK inhibitor tyrphostin (1 micromol/L) suppressed RC-4B/C cell proliferation and blocked the effect of IL-2 on RC-4B/C cells. After the PKA signaling pathway was inhibited by specific PKA inhibitor H-9 (1 micromol/L), the proliferation rate of RC-4B/C cells increased significantly. H-9 also enhanced the stimulation of IL-2 on RC-4B/C cell growth. Anti-estrogen tamoxifen (1 micromol/L) had no significant effect on the action of IL-2 on the proliferation of RC-4B/C cells. In conclusion, it is suggested that IL-2 modulates the proliferation of the cultured RC-4B/C pituitary adenoma cell line, and the action is closely related with the PTK and PKA signaling pathway.
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PMID:[Interleukin-2 stimulates the proliferation of cultured RC-4B/C pituitary adenoma cell line]. 1195 61


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