Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Heat shock protein 90 (hsp90) is a chaperone required for the proper folding and trafficking of many proteins involved in signal transduction. We tested whether hsp90 plays a role as a chaperone for GC-A, the membrane guanylate cyclase that acts as a receptor for atrial natriuretic peptide (ANP). When cultured cells expressing recombinant GC-A were treated with geldanamycin, an inhibitor of hsp90 function, the ANP-stimulated production of cyclic GMP was inhibited. This suggested that hsp90 was required for GC-A processing and/or stability. A physical association between hsp90 and GC-A was demonstrated in coimmunoprecipitation experiments. Treatment with geldanamycin disrupted this association and led to the accumulation of complexes containing GC-A and heat shock protein 70 (hsp70). Protein folding pathways involving hsp70 and hsp90 include several pathway-specific co-chaperones. Complexes between GC-A and hsp90 contained the co-chaperone p50(cdc37), typically found associated with protein kinase.hsp90 heterocomplexes. GC-A immunoprecipitates did not contain detectable amounts of Hop, FKBP51, FKBP52, PP5, or p23, all co-chaperones found in hsp90 complexes with other signaling proteins. The association of hsp90 and p50(cdc37) with GC-A was dependent on the kinase homology domain of this receptor but not on its ANP-binding, transmembrane, or guanylate cyclase domains. The data suggest that GC-A is regulated by hsp90 complexes similar to those involved in the maturation of protein kinases.
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PMID:Regulation of the atrial natriuretic peptide receptor by heat shock protein 90 complexes. 1115 73

The cyclins are a family of proteins that are centrally involved in cell cycle regulation and which are structurally identified by conserved "cyclin box" regions. They are regulatory subunits of holoenzyme cyclin-dependent kinase (CDK) complexes controlling progression through cell cycle checkpoints by phosphorylating and inactivating target substrates. CDK activity is controlled by cyclin abundance and subcellular location and by the activity of two families of inhibitors, the cyclin-dependent kinase inhibitors (CKI). Many hormones and growth factors influence cell growth through signal transduction pathways that modify the activity of the cyclins. Dysregulated cyclin activity in transformed cells contributes to accelerated cell cycle progression and may arise because of dysregulated activity in pathways that control the abundance of a cyclin or because of loss-of-function mutations in inhibitory proteins.Analysis of transformed cells and cells undergoing mitogen-stimulated growth implicate proteins of the NF-kappaB family in cell cycle regulation, through actions on the CDK/CKI system. The mammalian members of this family are Rel-A (p65), NF-kappaB(1) (p50; p105), NF-kappaB(2) (p52; p100), c-Rel and Rel-B. These proteins are structurally identified by an amino-terminal region of about 300 amino acids, known as the Rel-homology domain. They exist in cytoplasmic complexes with inhibitory proteins of the IkappaB family, and translocate to the nucleus to act as transcription factors when activated. NF-kappaB pathway activation occurs during transformation induced by a number of classical oncogenes, including Bcr/Abl, Ras and Rac, and is necessary for full transforming potential. The avian viral oncogene, v-Rel is an NF-kappaB protein. The best explored link between NF-kappaB activation and cell cycle progression involves cyclin D(1), a cyclin which is expressed relatively early in the cell cycle and which is crucial to commitment to DNA synthesis. This review examines the interactions between NF-kappaB signaling and the CDK/CKI system in cell cycle progression in normal and transformed cells. The growth-promoting actions of NF-kappaB factors are accompanied, in some instances, by inhibition of cellular differentiation and by inhibition of programmed cell death, which involve related response pathways and which contribute to the overall increase in mass of undifferentiated tissue.
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PMID:NF-kappaB and cell-cycle regulation: the cyclin connection. 1131 20

The expression of VCAM1 is up-regulated in renal proximal tubular epithelial cells (TEC) in a variety of inflammatory renal diseases, a prominent example of which is acute renal allograft rejection. VCAM1 may play an important role in these diseases because it binds to the integrins very late Ag-4 and alpha(4)beta(7) on lymphocytes and monocytes, thereby providing a potential mechanism to recruit these leukocytes to sites of inflammation. The molecular mechanisms underlying VCAM1 regulation in renal TEC are essentially unknown. We now report that VCAM1 mRNA is dramatically up-regulated in C1, a cell line derived from renal TEC, on exposure to TNF-alpha. Two NF-kappaB binding sites in the VCAM1 promoter are critical for the TNF-alpha-induced VCAM1 transcriptional up-regulation, and both sites bind to p65-p50 NF-kappaB complexes. TNF-alpha induces activation of inhibitor of NF-kappaB (IkappaB) kinase-beta (IKK-beta), a protein kinase that phosphorylates the NF-kappaB inhibitor IkappaB, and thereby targets the latter for degradation via the ubiquitin-proteasome pathway. Moreover, dominant negative versions of IKK inhibit TNF-alpha activation of a VCAM1 promoter reporter. We conclude that the IKK/NF-kappaB pathway is critical in the TNF-alpha-induced up-regulation of VCAM1 mRNA in renal TEC.
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PMID:I kappa B kinase is critical for TNF-alpha-induced VCAM1 gene expression in renal tubular epithelial cells. 1135 43

Exposure of renal tubular epithelial cells to shiga toxin 2 (Stx-2) causes cytotoxicity, and the potency of this toxin is enhanced in the presence of tumor necrosis factor-alpha (TNF-alpha). It has been shown that Stx-2 induces TNF-alpha production and that activation of beta(2)-adrenoceptors downregulates TNF-alpha. However, little is known about the signaling pathway by which beta(2)-adrenoceptor agonists suppress the Stx-2-induced TNF-alpha gene transcription. The possible signaling components involved in this pathway were investigated. Human adenocarcinoma-derived renal tubular epithelial cells (ACHN) were exposed to Stx-2 in the presence or absence of a beta(2)-adrenoceptor agonist. Mitogen-activated protein kinase (MAPK), activating protein-1 (AP-1), and nuclear factor-kappa B (NF-kappa B) were measured to evaluate the regulatory mechanisms involved in TNF-alpha gene transcription. Stx-2 (4 pg/ml) stimulated MAPK (p42/p44, p38) and AP-1 and increased TNF-alpha promoter activity by 2.4-fold. The increase in TNF-alpha was attenuated by both a p42/p44 inhibitor, PD098059 (10(-6) M), and a p38 inhibitor, SB203580 (10(-6) M), and AP-1-binding activity was inhibited by PD098059. Terbutaline (10(-6) M to 10(-8) M) suppressed MAPK (p42/p44, p38), NF-kappa B (p50, p65), and TNF-alpha promoter activity in a dose-dependent way that was prevented by the beta(2)-adrenoceptor antagonist, ICI118,551. However, inhibition of MAPK (p42/p44) and TNF-alpha promoter activity was partially prevented by the cAMP-protein kinase (PKA) inhibitors, H-89 (5 x 10(-6) M) and KT5720 (10(-5) M), whereas the suppression of p38 MAPK or NF-kappa B (p50) was not blocked by these inhibitors. The suppression of NF-kappa B (p65) was completely overcome by H-89 or KT5720. In summary, the downregulation of TNF-alpha transcription by terbutaline was mediated by an inhibitory effect of beta(2)-adrenoceptor activation on MAPK (p42/p44, p38) and NF-kappa B (p50/p65), which were exerted through a cAMP-PKA pathway and a cAMP-independent mechanism. It is likely that cAMP-PKA and MAPK (p42/p44, p38) may play a critical role in the regulation of the Stx-2-induced TNF-alpha transcription via beta(2)-adrenoceptor activation.
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PMID:Activation of beta(2)-adrenoceptor prevents shiga toxin 2-induced TNF-alpha gene transcription. 1167 5

Signal transduction pathways that lead to the modulation of genes related to survival and repair mechanisms are activated in neurons that survive injury. These protein kinase/phosphatase cascades converge on transcription factors, the DNA binding proteins that directly regulate gene expression. In this study we examined expression of the NF-kappaB p50 subunit in the rat hippocampus 7 days after injury caused by middle cerebral artery occlusion or trimethyltin treatment. We found increased levels of p50 in neurons throughout the hippocampus after both treatments, localized not only in cell bodies but also in processes. At the 7-day time point, Fluoro-Jade histochemistry revealed hippocampal neurodegeneration in trimethyltin-treated rats but not in those lesioned by middle cerebral artery occlusion. p50 was not expressed in Fluoro-Jade-positive degenerating cells, supporting the role of this transcriptional subunit in neurosurvival. Because phosphorylation of the inhibitor IkappaB protein by IkappaB kinase is the classic step in NF-kappaB activation, phospho-IkappaBalpha immunoreactivity was examined as an indication of IkappaB kinase activity. Levels of phospho-IkappaBalpha were increased in neurons throughout the hippocampus 7 days postinjury. Immunoblotting for phospho-IkappaBalpha demonstrated increased levels 1 day postinjury that remained elevated for at least 7 days. These data suggest that NF-kappaB signal transduction is involved in an adaptive response of neurons that survive injury.
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PMID:NF-kappaB p50 is increased in neurons surviving hippocampal injury. 1171 55

The 90-kDa heat shock protein (Hsp90), the target of the ansamycin class of anti-cancer drugs, is required for the conformational activation of a specific group of signal transducers, including Raf-1. In this report we have identified a 75-kDa Raf-associated protein as Hsp90N, a novel member of the Hsp90 family. Intriguingly, the ansamycin-binding domain is replaced in Hsp90N by a much shorter, hydrophobic sequence, preceded by a putative myristylation signal. We demonstrate that, although much less abundant, Hsp90N binds Raf with a higher affinity than Hsp90. In sharp contrast to Hsp90, Hsp90N does not associate with p50(cdc37), the Hsp90 kinase cofactor. Hsp90N was found to activate Raf in transiently transfected cells, while Rat F111 fibroblasts stably transfected with Hsp90N exhibited elevated activity of the Raf and downstream ERK kinases. This may be due to Raf binding to myristylated Hsp90N, followed by Raf translocation to the membrane. To examine whether Hsp90N could therefore substitute for Ras in Raf recruitment to the cell membrane, Hsp90N was transfected in c-Ras-deficient, 10T1/2-derived preadipocytes. Our results indicate that, as shown before for activated Ras or Raf, the introduction of even low levels of Hsp90N through transfection in c-Ras-deficient preadipocytes causes a dramatic block of differentiation. Higher levels of Hsp90N expression resulted in neoplastic transformation, including interruption of gap junctional, intercellular communication, and anchorage-independent proliferation. These results indicate that the observed activation of Raf by Hsp90N has a profound biological effect, which is largely c-Ras-independent. With the recent finding that p50(cdc37) is tumorigenic in transgenic mice, these results reinforce the intriguing observation that the family of heat shock proteins represents a novel class of molecules with oncogenic potential.
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PMID:The role of Hsp90N, a new member of the Hsp90 family, in signal transduction and neoplastic transformation. 1175 6

Tumor necrosis factor (TNF) is one of the most potent activators of nuclear transcription factor NF-kappaB, c-Jun N-terminal protein kinase (JNK), and apoptosis in a wide variety of cells. The biological effects of TNF are mediated through sequential interactions of various cytoplasmic proteins with intracellular domains of TNF receptors. Whether signal transducer and activator of transcription-1 (STAT1), which mediates interferon (IFN) signaling, also plays any role in the TNF-mediated activation of NF-kappaB, JNK, and apoptosis has not been established. Here, we report our investigation of the role of STAT1 in TNF signaling using STAT1-deficient U3A and STAT1-stably transfected U3A-PSG91 cells. IFNalpha inhibited the proliferation of STAT1-expressing U3A-PSG91 cells but had no effect on STAT1-negative U3A cells. TNF alone, even up to 10 nM, had no effect on the proliferation of either U3A-PSG91 or U3A cells. Irrespective of STAT1 status, TNF induced cytotoxic effects in the presence of cycloheximide (CHX) in both cell types. Additionally, TNF-induced caspase-3 and caspase-8 activation and TNF-induced PARP cleavage were unaffected by the presence or absence of STAT1. TNF activated NF-kappaB, consisting of p50 and p65, in both U3A and U3A-pSG91 cells in a dose- and time-dependent manner, but the degree and rate of activation were slightly lower in U3A cells, as were IkappaBalpha degradation and NF-kappaB-dependent reporter gene expression. STAT1 was, however, required for IFNalpha-mediated downregulation of TNF-induced NF-kappaB activation. TNF activated JNK in both cell types, but dose and time of exposure required for optimum activation differed slightly. Thus, overall our results indicate that STAT1 plays a minimal role in TNF-mediated cellular responses.
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PMID:Lack of requirement of STAT1 for activation of nuclear factor-kappaB, c-Jun NH2-terminal protein kinase, and apoptosis by tumor necrosis factor-alpha. 1183 5

In vivo activation of client proteins by Hsp90 depends on its ATPase-coupled conformational cycle and on interaction with a variety of co-chaperone proteins. For some client proteins the co-chaperone Sti1/Hop/p60 acts as a "scaffold," recruiting Hsp70 and the bound client to Hsp90 early in the cycle and suppressing ATP turnover by Hsp90 during the loading phase. Recruitment of protein kinase clients to the Hsp90 complex appears to involve a specialized co-chaperone, Cdc37p/p50(cdc37), whose binding to Hsp90 is mutually exclusive of Sti1/Hop/p60. We now show that Cdc37p/p50(cdc37), like Sti1/Hop/p60, also suppresses ATP turnover by Hsp90 supporting the idea that client protein loading to Hsp90 requires a "relaxed" ADP-bound conformation. Like Sti1/Hop/p60, Cdc37p/p50(cdc37) binds to Hsp90 as a dimer, and the suppressed ATPase activity of Hsp90 is restored when Cdc37p/p50(cdc37) is displaced by the immunophilin co-chaperone Cpr6/Cyp40. However, unlike Sti1/Hop/p60, which can displace geldanamycin upon binding to Hsp90, Cdc37p/p50(cdc37) forms a stable complex with geldanamycin-bound Hsp90 and may be sequestered in geldanamycin-inhibited Hsp90 complexes in vivo.
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PMID:Regulation of Hsp90 ATPase activity by the co-chaperone Cdc37p/p50cdc37. 1191 74

The cellular chaperone Hsp90 has been shown to associate with the reverse transcriptase (RT) of the duck hepatitis B virus and is required for RT functions. However, the molecular basis for the specific interaction between the RT and Hsp90 remains unknown. Comparison of protein compositional properties suggests that the RT is highly related to the protein kinase c-Raf, which interacts with Hsp90 via the cochaperone p50 (CDC37). We tested whether the RT, like c-Raf, is specifically recognized by p50. Immunoprecipitation and pull-down assays showed that p50 or p50deltaC, a p50 mutant defective in Hsp90 binding, could interact specifically with the RT both in vitro and in vivo, indicating that p50 can bind the RT independently of Hsp90. Furthermore, purified p50 and p50deltaC interacted directly with purified RT. The importance of p50-RT interaction for RT functions was underscored by 1) inhibition of protein-primed initiation of reverse transcription by p50deltaC in vitro and 2) stimulation of viral DNA replication and RNA packaging by p50 and their inhibition by p50deltaC in transfected cells. These results suggest that p50 can function as a cellular cofactor for the hepadnavirus RT by mediating the interaction between the RT and Hsp90.
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PMID:Role of p50/CDC37 in hepadnavirus assembly and replication. 1198 22

Parathyroid hormone (PTH)-related protein (PTHrP) seems to affect bone resorption by interaction with bone cytokines, among them interleukin-6 (IL-6). Recent studies suggest that nuclear factor (NF)-kappaB activation has an important role in bone resorption. We assessed whether the N-terminal fragment of PTHrP, and its C-terminal region, unrelated to PTH, can activate NF-kappaB, and its relationship with IL-6 gene induction in different rat and human osteoblastic cell preparations. Here we present molecular data demonstrating that both PTHrP (1-36) and PTHrP (107-139) activate NF-kappaB, leading to an increase in IL-6 mRNA, in these cells. Using anti-p65 and anti-p50 antibodies, we detected the presence of both proteins in the activated NF-kappaB complex. This effect induced by either the N- or C-terminal PTHrP domain in osteoblastic cells appears to occur by different intracellular mechanisms, involving protein kinase A or intracellular Ca(2+)/protein kinase C activation, respectively. However, the effect of each peptide alone did not increase further when added together. Our findings lend support to the hypothesis that the C-terminal domain of PTHrP, in a manner similar to its N-terminal fragment, might stimulate bone resorption. These studies also provide further insights into the putative role of PTHrP as a modulator of bone remodeling.
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PMID:Both N- and C-terminal domains of parathyroid hormone-related protein increase interleukin-6 by nuclear factor-kappa B activation in osteoblastic cells. 1200 Jul 45


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