Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Microtubule-associated protein tau from Alzheimer brain has been shown to be phosphorylated at several ser/thr-pro and ser/thr-X sites (Hasegawa, M. et al., J. Biol. Chem. 267, 17047-17054, 1992). Several proline-dependent protein kinases (PDPKs) (MAP kinase, cdc2 kinase, glycogen synthase kinase-3, tubulin-activated protein kinase, and 40 kDa neurofilament kinase) are implicated in the phosphorylation of the ser-thr-pro sites. The identity of the kinase(s) that phosphorylate the ser/thr-X sites are unknown. To identify the latter kinase(s) we have compared the phosphorylation of bovine tau by several brain protein kinases. Stoichiometric phosphorylation of tau was achieved by casein kinase-1, calmodulin-dependent protein kinase II, Gr kinase, protein kinase C and cyclic AMP-dependent protein kinase, but not with casein kinase-2 or phosphorylase kinase. Casein kinase-1 and calmodulin-dependent protein kinase II were the best tau kinases, with greater than 4 mol and 3 mol 32P incorporated, respectively, into each mol of tau. With the sequential addition of these two kinases, 32P incorporation approached 6 mol. Peptide mapping revealed that the different kinases largely phosphorylate different sites on tau. After phosphorylation by casein kinase-1, calmodulin-dependent protein kinase II, Gr kinase, cyclic AMP-dependent protein kinase and casein kinase-2, the mobility of tau isoforms as detected by SDS-PAGE was decreased. Protein kinase C phosphorylation did not produce such a mobility shift. Our results suggest that one or more of the kinases studied here may participate in the hyperphosphorylation of tau in Alzheimer disease.(ABSTRACT TRUNCATED AT 250 WORDS)
Mol Cell Biochem 1994 Feb 23
PMID:Comparison of the phosphorylation of microtubule-associated protein tau by non-proline dependent protein kinases. 803 84

During chronic pain and inflammation, prodynorphin gene expression is elevated in the spinal cord. To characterize the molecular regulation of prodynorphin gene expression, we examined an AP-1/CRE-like element, TGCGTCA, located at -1545 in the prodynorphin gene (the DYNCRE3 site). Previous work in our laboratory demonstrated by gel shift analysis that Fos and non-Fos-containing complexes formed with oligonucleotides containing this element. To examine the functional significance of this site, constructs containing variable length regions of the prodynorphin promoter were transiently transfected into PC12 or HeLa cells. Constructs containing the DYNCRE3 site consistently permitted higher levels of transcriptional activity than those lacking this site. Furthermore, placement of upstream regions containing the DYNCRE3 site adjacent to the minimal promoter yielded transcriptional activity much greater than that in the presence of the native constructs. PC12 cells transfected with constructs containing the DYNCRE3 site responded to a far greater degree to forskolin stimulation than those transfected with constructs that did not contain this site. Mutation of the DYNCRE3 site (CTcgtca) markedly reduced forskolin-induced increases in transcriptional activity. The phorbol ester 12-O-tetradecanoylphorbol 13-acetate produced little or no change in transcriptional activity. By examining successively more isolated fragments of prodynorphin promoter and by mutational analysis, we identify and characterize a 7-bp site, DYNCRE3, which, though largely unaffected by stimulations of the PKC pathway, dramatically responds to stimulations via the PKA second messenger pathway.
Mol Cell Neurosci 1994 Jun
PMID:Basal and inducible transcriptional activity of an upstream AP-1/CRE element (DYNCRE3) in the prodynorphin promoter. 808 22

Immunocytofluorescence studies demonstrated that alpha-PKC is concentrated in focal contacts of REF52 cells but not in their SV40-transformed derivatives [Jaken et al. (1989) J. Cell Biol. 109, 697-704; Hyatt & Jaken (1990) Mol. Carcinog. 3, 45-53]. Discrete localizations imply that PKC is targeted to these areas possibly via protein-protein interactions. We have used an overlay assay to detect alpha-PKC binding proteins. The molecular interactions between alpha-PKC and the binding proteins depended on phospholipid and either calcium or phorbol esters. Unlike the kinase activity, binding activity was detected in the absence of added calcium, indicating that calcium, which is necessary for phosphorylation of most substrates, is not required for binding. Vinculin and talin, two focal contact proteins, bound alpha-PKC. REF52 cells express several annexins (I, II, and VI) which bind PKC. Both annexin I expression and vinculin expression were decreased in SV40-REF52 cells. The two major REF52 cell binding proteins (p71 and p > 200 kDa) were also down-regulated in the transformed cells, indicating transformation-sensitive regulation of PKC binding protein activity.
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PMID:Identification and characterization of alpha-protein kinase C binding proteins in normal and transformed REF52 cells. 811 Jul 54

1. Cl- ion outward permeation across microdissected Deiters' neuron plasma membranes is augmented by GABA on the membrane cytoplasmic side. When these neurons are preincubated with a PKC activator, phorbol-12,13-dibutyrate (PdBu), there is a complex pattern of effects on basal and GABA-activated 36Cl- in-->out permeation. A distinct fact is an increase in basal Cl- passage and a disappearance of the 10(-6) M GABA effect at [PdBu] = 0.1 microM. 2. Likewise, 0.1 microM oleylacetylglycerol (OAG) treatment erases the effect completely, further supporting a role for PKC in modulating GABA-stimulated Cl- in-->out permeation. 3. The inactive ester, phorbol-12,13-didecanoate (Pdd), at 0.1 microM, does not affect GABA stimulation of Cl- passage. 4. High concentration (15-20 microM) of OAG and PdBu block the "intracellular" GABA efefct. However, the 20 microM PdBu effect is reversed by 30 microM H7. 5. These results indicate a role of endogenous PKC in Cl- extrusion by GABAA receptors on the cytoplasmic side of the Deiters' neuron membrane.
Cell Mol Neurobiol 1993 Oct
PMID:The increase in Cl- permeation across the Deiters' neuron membrane by GABA on its cytoplasmic side is abolished by protein kinase C (PKC) activators. 811 26

Intracellular effector systems which utilize PKA and PKC can be pharmacologically activated by forskolin and phorbol 12-myristate 13-acetate (PMA) and appear to be important for regulation of steroidogenesis by cells of the corpus luteum. In this study the effect of pharmacologic activation of PKA (forskolin) or PKC (PMA) on the activity of adenylate cyclase, cholesterol esterase, P450 cholesterol side chain cleavage (P450scc) and 3 beta-hydroxysteroid dehydrogenase/delta 5, delta 4 isomerase (3 beta HSD) was determined. Basal adenylate cyclase activity (as measured by intracellular and secreted cAMP) was extremely low in both large and small luteal cells. Forskolin stimulated adenylate cyclase activity in both large and small luteal cells but progesterone production was increased only in small cells. PMA inhibited progesterone production by large and forskolin-stimulated small cells without altering adenylate cyclase activity. Basal cholesterol esterase activity was greater in small than in large cells and was stimulated by forskolin only in small cells. PMA did not significantly alter cholesterol esterase activity in either cell type. Activity of P450scc or 3 beta HSD was measured by conversion of hydroxylated cholesterol derivatives (P450scc) or pregnenolone (3 beta HSD) to progesterone. Although basal progesterone production was 47 times greater in large than small cells, there was only 5.1 (P450scc) and 6.4 (3 beta HSD) times greater enzyme activity in large than in small luteal cells. Activation of PKA and/or PKC did not alter the activity of P450scc or 3 beta HSD in either cell type.(ABSTRACT TRUNCATED AT 250 WORDS)
Mol Cell Endocrinol 1993 Nov
PMID:Steroidogenic enzyme activity after acute activation of protein kinase (PK) A and PKC in ovine small and large luteal cells. 814 91

The most potent, physiologic activator of proopiomelanocortin (POMC) gene transcription is corticotropin releasing hormone (CRH) and increased intracellular cAMP is critical for this effect. The 5'-flanking region of the murine POMC gene has several potential binding sites for regulatory proteins. To characterize the region between nucleotides -141 and -106, which includes a TRE-like site and an adjacent AP-2 consensus sequence, and to study its role in signal-transcription coupling, gel mobility shift assays and transient expression of CAT chimeras were performed. In transient transfections of AtT-20 cells with pCATp-141/-106, CRH treatment led to significant increases in CAT expression compared with CRH treatment of cells transfected with the enhancerless vector. However, no response to direct activation of cAMP dependent protein kinase or protein kinase C was detected. Despite the high homology of the sequence -137/-131 to the consensus AP-1 binding site (TRE), the nuclear factor(s) in AtT-20 cells binding to this region appears to be different than authentic AP-1 since neither a competitor oligonucleotide having the authentic TRE sequence nor antibodies against Jun or Fos affected the gel shift pattern of a probe having the -137/-131 sequence. We conclude that the -141 to -106 region of the murine POMC gene contains a functional CRH responsive element and that second messenger systems that transduce the CRH signal to this element do not exert their actions solely through activation of PKA or PKC.
Mol Cell Endocrinol 1993 Nov
PMID:Characterization of a corticotropin releasing hormone responsive region in the murine proopiomelanocortin gene. 814

Tumor necrosis factor-alpha (TNF) induces clustering of theca-interstitial cells (TIC) isolated from immature, hypophysectomized rats, while inhibiting luteinizing hormone (LH)-stimulated androstenedione in vitro. Stimulators of PKC, 1-oleoyl-2-acetyl-sn-glycerol (OAG, 50 and 100 microM) and phorbol-12-myristate-13-acetate (PMA, 50 nM), caused TIC clustering by 6 days in vitro. Clustering induced by these compounds resembled that induced by TNF. The protein kinase inhibitor, staurosporine at 1 and 10 nM, impaired TNF-induced TIC clustering for 6 days, as did the protein kinase inhibitor, 1-(5-isoquinolinesulfonyl)-2-methylpiperizine dihydrochloride (H-7); conversely, the protein kinase inhibitor, chelerythrine chloride (0.1, 1.0 or 10 microM), did not attenuate TNF-directed clustering. The protein kinase inhibitors did not reverse the suppression of LH-stimulated androstenedione by TNF. Inhibitors of the EGF receptor PTK, A23 (10, 50, or 100 microM) and A46 (0.1, 1.0, 10, or 50 microM), impaired TNF-induced TIC clustering, while TNF suppression of LH-directed androstenedione was unaffected. EGF-induced TIC clustering was also impaired by A46, while A23 was less effective. Both A23 and A46 blocked EGF attenuation of LH-directed androstenedione after 4 days. When challenged with TNF (1 ng/ml) or PMA (50 nM), PKC activity increased in TIC. A23 (50 microM) and A46 (10 microM) each alone blocked the TNF-associated increase in PKC activity; however, PKC activity attributable to PMA was unaffected by A46. Together, these results suggest that TNF-induced TIC clustering involves activation of PTK which directs subsequent increases in PKC activity; however, mechanisms by which TNF inhibits LH-stimulated steroidogenesis remains elusive.
Mol Cell Endocrinol 1993 Nov
PMID:Involvement of protein kinase C and protein tyrosine kinase pathways in tumor necrosis factor-alpha-induced clustering of ovarian theca-interstitial cells. 814 4

Protein F1/GAP43 is neuron-specific, associated with neurite outgrowth during development and a substrate for PKC. This protein is present in high levels in serotonergic neurons which in culture sprout in response to the glial-derived S100b, the beta-beta homodimer. As an initial step in determining whether S100b acts on F1/GAP43 we studied the regulation by S100b of PKC phosphorylation of F1/GAP43. Either the S100b or a mixture of S100a and S100b, both from a brain glial cell source, inhibited in vitro phosphorylation of purified F1/GAP43 by purified PKC in a dose-dependent manner. Using recombinant PKC subtypes, purified S100b preferentially inhibited the F1/GAP43 phosphorylation by the beta subtype. The IC50 of S100b for beta I and beta II PKC was 8 microM while for alpha and gamma PKC it was 64 microM. S100b inhibition was thus subtype-selective. Histone III-S phosphorylation by the four PKC subtypes was not inhibited by S100b. S100b inhibition was thus substrate-selective. Moreover, the effect of S100b on phosphorylation could not be explained by a direct inhibition of kinase activity. Together with earlier studies implicating a role for S100 in synaptic plasticity and neurite outgrowth, the present results suggest that S100b may regulate such functions through its inhibition of neuron-specific PKC substrate (F1/GAP43) phosphorylation. The regulation of this neuron-specific substrate phosphorylation by glial S100 suggests the potential for a novel neuro-glial interaction. Finally, the location of S100 gene on chromosome 21, trisomic in Down's syndrome, and over-expressed in this disorder, as well as in Alzheimer's disease, suggests a link to cognitive impairments in human.
Brain Res Mol Brain Res 1994 Jan
PMID:Glial-derived S100b protein selectively inhibits recombinant beta protein kinase C (PKC) phosphorylation of neuron-specific protein F1/GAP43. 816 23

To evaluate the response of an epithelial barrier to a moderate but sustained oxidative stress, we cultured monolayers of Madin Darby canine kidney cells on microporous filters and exposed them to the hypoxanthine-xanthine oxidase (HX-XO) reaction. The transepithelial permeability coefficient for mannitol (Pm) was assessed as a marker of paracellular permeability. When the oxidative stress was limited in intensity and duration (production of 10 nmol/ml/min O2- with generation of 467 +/- 30 nmol/ml H2O2 over 1 h), we observed an increase of Pm with a delay of several hours (324 +/- 65% of baseline by 6 h, P < 0.005). There was complete return to control values by 24 h. The increase of Pm did not appear to be related to a depletion of cellular ATP. Protein kinase C (PKC) activity did not increase, and the rise in Pm was not prevented by CGP 41,251, a specific inhibitor of PKC. By contrast, CGP 41,251 inhibited the Pm increase that was elicited by PDBU, a phorbol ester that activates PKC. In our model, we conclude that a reversible increase of paracellular permeability occurs after oxidative stress independently of ATP depletion or PKC activation. Other, as yet unknown mechanisms have to be involved in this process.
Am J Respir Cell Mol Biol 1993 Nov
PMID:Oxidative stress causes a protein kinase C-independent increase of paracellular permeability in an in vitro epithelial model. 821 90

Protein kinase C is reported to exist in two membrane-bound states: a reversible one which can be dissociated by calcium chelators (membrane-associated form) and an irreversible one which is chelator stable (membrane-inserted form). In the present work the effects of a naturally occurring polyamine (spermine) on the membrane-associated and membrane-inserted forms of protein kinase C were investigated using a reconstituted system consisting of partially purified protein kinase C from rat brain and phospholipid vesicles of defined composition. The active membrane-bound complex was conveniently determined by its ability to bind radioactive phorbol ester with an exact 1:1 stoichiometry. Our experimental data show that, in the absence of calcium ions, the amount of enzyme bound to phospholipids vesicles was dramatically reduced by the presence of spermine whereas the PDBu binding affinity was not significantly affected. The addition of the divalent cation increased the affinity of phorbol ester for the active complex but had no effect on Nmax; spermine added in this experimental conditions was no longer able to decrease the total number of enzyme molecules bound to liposomes. Moreover gel filtration experiments of the protein kinase C-phospholipids complex formed in the presence of calcium, indicated that polyamine added during the association process was able to reduce the extent of enzyme insertion into liposomes. Since the increase in phospholipid concentration resulted in a higher level of non-dissociable protein kinase C-liposomes complex we propose that spermine, complexing to membrane binding sites both in the absence and in the presence of Ca++, could promote binding conditions that oppose to the formation of the inserted form of the enzyme. As a consequence the distribution between the reversible and the irreversible membrane-bound forms of protein kinase C is affected.
Mol Cell Biochem 1993 Jul 07
PMID:Effect of spermine on membrane-associated and membrane-inserted forms of protein kinase C. 823 73


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