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)

Erythroid colony formation in response to erythropoietin (EPO) stimulation is enhanced by costimulating the cells with prostaglandin-E2 (PGE2). The present study further analyzed the underlying mechanisms and demonstrated that EPO-mediated STAT5 transactivation in the erythroid AS-E2 cell line was enhanced 6-fold by PGE2 (10 microM), without affecting the STAT5 tyrosine phosphorylation or STAT5-DNA binding. Moreover, the PGE2-enhancing effect was independent of STAT5 serine phosphorylation. In AS-E2 cells STAT5 is constitutively phosphorylated on Ser780 (STAT5A) and EPO-dependently phosphorylated on Ser726/731 (STAT5A/STAT5B), but overexpression of STAT5 serine mutants did not affect STAT5 transactivation. In addition, PGE2 did not affect STAT5 serine phosphorylation. Instead, the stimulatory effect of PGE2 on STAT5 signaling could be mimicked by dibutyryl-cyclic adenosine monophosphate (cAMP) and the phosphodiesterase inhibitor IBMX, suggesting that the effect was mediated by cAMP. Activation of the cAMP pathway resulted in cAMP-response element binding protein (CREB) phosphorylation, which was sustained in the presence of EPO plus PGE2 and transient on EPO stimulation alone. The costimulatory effect of PGE2 on EPO-mediated STAT5 transactivation was inhibited by overexpression of serine-dead CREB or protein kinase A (PKA) inhibitor (PKI), in contrast to EPO-mediated transactivation, which was PKA independent. Furthermore, CREB-binding protein (CBP)/p300 was shown to be involved in EPO-mediated STAT5 transactivation, and a CBP mutant with increased affinity for CREB resulted in an additional enhancement of the PGE2 effect. Finally, we demonstrated that the STAT5 target genes Bcl-X, SOCS2, and SOCS3 were up-regulated by costimulation with PGE2. In summary, these studies demonstrate that PGE2 enhancement of EPO-induced STAT5 transactivation is mediated by the cAMP/PKA/CREB pathway.
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PMID:Prostaglandin-E2 enhances EPO-mediated STAT5 transcriptional activity by serine phosphorylation of CREB. 1209 37

The major protein component of the cornified cell envelope barrier structure of the epidermis is loricrin, and it is expressed late during terminal differentiation in epidermal keratinocytes. We have previously shown that an AP1 site located in the proximal promoter region (position -55) is essential for human loricrin promoter activity (Rossi, A., Jang, S-I., Ceci, R., Steinert, P. M., and Markova, N. G. (1998) J. Invest. Dermatol. 110, 34-40). In this study we show that its regulation requires complex cooperative and competitive interactions between multiple transcription factors in keratinocytes located in different compartments of the epidermis. We show that as few as 154 base pairs of 5'-upstream sequences from the cap site can direct the keratinocyte-specific expression in cultured keratinocytes. Mutation and DNA-protein analyses show that Sp1, c-Jun, an unidentified regulator, and the co-activator p300/CREB-binding protein up-regulate whereas Sp3, CREB-1/CREMalpha/ATF-1, Jun B, and an AP2-like protein (termed the keratinocyte-specific repressor-1 (KSR-1)) suppress loricrin promoter activity. We show that CREB protein can compete with c-Jun for the AP1 site and repress loricrin promoter activity. We show here that the protein kinase A pathway can activate loricrin expression by manipulation of the Sp1, Sp3, and KSR-1 levels in the nucleus. Thus, in undifferentiated cells, loricrin expression is suppressed by Jun B, Sp3, and KSR-1 proteins. But in advanced differentiated cells, levels of Sp3, KSR-1, and CREB proteins are lower; the unidentified regulator protein can bind; Sp1 and c-Jun are increased; and then p300/CBP is recruited. Together, these events allow loricrin transcription to proceed. Indeed, the synergistic effects of the Sp1, c-Jun, and p300 factors indicate that p300/CBP might act as bridge to form an active transcription complex.
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PMID:Loricrin expression in cultured human keratinocytes is controlled by a complex interplay between transcription factors of the Sp1, CREB, AP1, and AP2 families. 1220 Apr 29

The ETS transcription factor ER81 is activated in response to many signals via mitogen-activated protein kinases (MAPKs). However, ER81 is not only phosphorylated on MAPK sites but also at other sites that impact on its transactivation potential. Here we describe that the 90-kDa ribosomal S6 kinase 1 (RSK1), a protein kinase downstream of the extracellular signal-regulated kinase (ERK) subclass of MAPKs, binds to ER81, phosphorylates it, and enhances ER81-dependent transcription. Two in vivo RSK1 phosphorylation sites within ER81, Ser(191) and Ser(216), were identified, whose mutation to alanine reduces ER81 activity upon ERK-MAPK stimulation. Furthermore, RSK1 activates the ER81 cofactor CREB-binding protein and may thereby augment ER81-dependent transcription. Similar to RSK1, the cAMP-dependent protein kinase A (PKA) phosphorylates ER81 on Ser(191)/Ser(216). Additionally, PKA targets ER81 on Ser(334) in vivo. Surprisingly, phosphorylation of Ser(334) severely reduces the DNA-binding ability of ER81 but also enhances the transactivation potential of ER81. These counteractive effects of PKA phosphorylation on ER81-dependent transcription may cause the selective up-regulation of promoters with high but not low affinity for ER81. Collectively, we have identified mechanisms for how two distinct signaling pathways with different effector protein kinases, RSK1 and PKA, converge on ER81, which may regulate ER81 function during development and tumorigenesis.
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PMID:Regulation of the ETS transcription factor ER81 by the 90-kDa ribosomal S6 kinase 1 and protein kinase A. 1221 13

The cAMP-dependent protein kinase (PKA) signaling pathway plays a major role in a number of pathophysiological conditions. However, there have been conflicting evidences regarding the action of cAMP/PKA on nuclear factor- kappaB (NF-kappaB). In this study, we have explored the effect of cAMP/PKA on NF-kappaBeta activity and determined its molecular mechanism. PKA activating agents or expression of the catalytic subunit of PKA (PKAc) inhibited the NF-kappaBeta-dependent reporter gene expression induced by tumor necrosis factor alpha (TNFalpha). PKA activators affected neither IkappaBalpha phosphorylation, IkappaBetaalpha degradation, nor the NF-kappaBeta/DNA binding. Expression of PKAc inhibited the transactivation potential of Gal4-p65 (286-551) suggesting that the inhibitory action of PKA is through the C-terminal transactivation domain of p65 but not by phosphorylation of the consensus PKA recognition site containing serine at position 276. Overexpression of coactivators, CBP (CREB-binding protein) and p300, failed to reverse the PKA-mediated inhibition of p65 transactivation. Thus, the inhibitory action of the cAMP/PKA pathway on the transcriptional activity of NF-kappaB appears to be exhibited by modifying the C-terminal transactivation domain of p65, either directly or indirectly.
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PMID:Inhibition of the NF-kappaB transcriptional activity by protein kinase A. 1223 May 68

Although increases in intracellular cAMP can stimulate estrogen receptor-alpha (ER alpha) activity in the absence of exogenous hormone, no studies have addressed whether ER beta can be similarly regulated. In transient transfections, forskolin plus 3-isobutyl-1-methylxanthine (IBMX), which increases intracellular cAMP, stimulated the transcriptional activities of both ER alpha and ER beta. This effect was blocked by the protein kinase A inhibitor H89 (N-(2-(p-bromocinnamylamino)-ethyl)-5-isoquinolinesulfonamide) and was dependent on an estrogen response element. A 12-O-tetradecanoylphorbol-13-acetate response element (TRE) located 5' to the estrogen response element was necessary for cAMP-dependent activation of gene expression by ER beta but not ER alpha, indicating that the former subtype requires a functional interaction with TRE-interacting factor(s) to stimulate transcription. Both p160 and CREB-binding protein coactivators stimulated cAMP-induced ER alpha and ER beta transcriptional activity. However, mutation of the two cAMP-inducible SRC-1 phosphorylation sites important for cAMP activation of chicken progesterone receptor or all seven known SRC-1 phosphorylation sites did not specifically impair cAMP activation of ER alpha. The E/F domains of ER alpha are sufficient for activation by forskolin/IBMX, and this is accompanied by an increase in receptor phosphorylation. In contrast, cAMP signaling reduces the phosphorylation of the corresponding region of ER beta, and this correlates with the lack of forskolin/IBMX stimulated transcriptional activity. Our data suggest that cAMP activation of ER alpha transcriptional activity is associated with receptor instead of SRC-1 phosphorylation. Moreover, differences in the cofactor requirements, domains of ER alpha and ER beta sufficient for forskolin/IBMX activation, and the effect of cAMP on receptor phosphorylation indicate that this signaling pathway utilizes distinct mechanisms to stimulate ER alpha and ER beta transcriptional activity.
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PMID:Mechanistic differences in the activation of estrogen receptor-alpha (ER alpha)- and ER beta-dependent gene expression by cAMP signaling pathway(s). 1256 49

Gonadal gene expression is regulated by pituitary hormones acting through the cAMP/protein kinase A (PKA) signal transduction pathway. The downstream molecular effectors of these signals, however, have yet to be fully understood. We have recently shown that cAMP stimulation of gonadal cells leads to phosphorylation of the transcription factor GATA-4, a key regulator of gonadal gene expression, thus suggesting that this factor might be a novel target for the cAMP/PKA signaling pathway. We now show that the rapid phosphorylation of GATA-4 induced by cAMP in vivo can be blocked by a PKA-specific inhibitor but not by mitogen-activated protein kinase inhibitors, indicating that GATA-4 is predominantly phosphorylated by PKA in response to cAMP in gonadal cells. In addition, using in vitro kinase assays, we show that PKA phosphorylation of GATA-4 occurs predominantly on an evolutionarily conserved serine residue located at position 261. Phosphorylation of GATA-4 Ser261 by PKA enhances its transcriptional activity on different gonadal promoters, an effect that was markedly reduced with a S261A mutant. Moreover, the S261A mutant blunted cAMP-induced promoter activity in gonadal cells. Finally, PKA-dependent phosphorylation of GATA-4 also led to enhanced recruitment of the CREB-binding protein coactivator. This recruitment and transcriptional cooperation were dramatically impaired with the S261A mutant. Thus, our results identify GATA-4 as a novel downstream effector of cAMP/PKA signaling in gonadal cells, where phosphorylation of Ser261 and recruitment of CREB-binding protein likely represent a key mechanism for conveying the cAMP responsiveness of gonadal genes that lack classical cAMP regulatory elements.
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PMID:Transcription factor GATA-4 is activated by phosphorylation of serine 261 via the cAMP/protein kinase a signaling pathway in gonadal cells. 1267 Sep 47

The Kruppel-like factor 5 (KLF5/IKLF) belongs to the Kruppel family of genes which bind GC-rich DNA elements and activate or repress their target genes in a promoter context and/or cellular environment-dependent manner. In the present study, we used the Gal4 fusion assay system to characterize the mechanism of transactivation by KLF5. We demonstrated that the transactivation function of KLF5 was enhanced by CREB-binding protein (CBP) and blocked by wild-type but not mutant E1A. Over expression of CBP reversed the inhibition effect of E1A. With various lengths of KLF5 fusion protein, the transactivation functions were localized to 156 amino acid residues at the N-terminal region and 133 amino acid residues adjacent to the Zn finger motif. We mapped the CBP and KLF5 interaction domain to the N-terminal region of CBP (amino acids 1-232) and the N-terminal region of KLF5 (amino acids 1-238) where one of the activation functions resides. The histone acetyltransferase (HAT) activity of CBP does not play a role in the transactivation function of KLF5 nor does it acetylate KLF5 in vitro. However, phosphorylation is important in KLF5 transactivation activity. Inhibition of protein kinase activity by H7 or calphostin C blocked both full-length and N-terminal fragment (amino acids 1-238) KLF5 activities. Mutation at a potential protein kinase C phosphorylation site within the CBP interaction domain of KLF5 reduces its transactivation function. Furthermore, using the GST pull-down approach, we showed that phosphorylation of KLF5 enhances its interaction with CBP. The results of the present study provide a mechanism for KLF5 transactivation function.
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PMID:Phosphorylation of Kruppel-like factor 5 (KLF5/IKLF) at the CBP interaction region enhances its transactivation function. 1268 70

Shear stress (SS), the tangential component of hemodynamic forces, modulates the expression of several genes in endothelial cells. However, no information is available about its effect on chromatin structure, which plays a key role in gene transcription. In this study, a link between SS and chromatin remodeling was established in human umbilical vein endothelial cells (HUVECs). HUVECs were exposed to SS of 10 dyne/cm2 per second, in the presence or absence of the histone deacetylase inhibitor trichostatin A, and assayed for histone H3 and histone H4 modifications. SS induced histone H3 serine phosphorylation at position 10 (S10) and lysine acetylation at position 14 (K14) but required trichostatin A to induce H3 phosphoacetylation and H4 acetylation. The phosphatidylinositol 3-kinase inhibitor wortmannin and the mitogen-activated protein kinase inhibitor PD98059 decreased SS-dependent histone H3 phosphorylation, without affecting its acetylation; the p38 inhibitor SB203580 reduced both H3 phosphorylation and acetylation, whereas the protein kinase A inhibitor PKI-tide reduced histone H3 acetylation. Remarkably, the abrogation of histone acetylation inhibited SS-dependent c-fos expression. SS also activated ribosomal S6 kinase-2 and mitogen- and stress-activated kinase-1 protein kinases and promoted the formation of a cAMP-responsive element-binding protein (CREB)/CREB-binding protein complex, providing the molecular basis for the increase in histone acetyltransferase activity observed in HUVECs exposed to SS. Finally, the effect of SS on chromatin remodeling was examined. In HUVECs exposed to SS, chromatin within c-fos and c-jun promoters was specifically immunoprecipitated by an antibody against acetylated histone H3 on K14. These results indicate that SS induces posttransduction modifications of histones; this is an early step toward the flow-dependent regulation of gene expression.
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PMID:Shear stress-mediated chromatin remodeling provides molecular basis for flow-dependent regulation of gene expression. 1280 38

The nucleoprotein structure of the mouse mammary tumor virus (MMTV) promoter defines its response to cAMP signaling. A stably replicating MMTV template in highly organized chromatin is repressed in the presence of cAMP, whereas a transiently transfected template with a disorganized structure is activated. In this study, we investigate the nature of the cAMP-induced signal(s) by which these opposing responses occur to gain insight into their mechanism. We demonstrate that the transcriptional changes observed at both templates are mediated through cAMP-dependent protein kinase A (PKA). In addition, the MMTV promoter lacks a consensus cAMP response element (CRE) and neither template requires cAMP response element-binding protein (CREB) to elicit a response to cAMP signaling. However, the responses of the two templates differ mechanistically in that the CREB-binding protein p300 potentiates activation from the transient template in a manner dependent on its Cys/His-rich region 3, but does not appear to affect the repression of the replicating chromatin template. Chromatin immunoprecipitation assays show that cAMP treatment results in a decrease in acetylation of histone H4, and in multiple modifications of histone H3 at specific nucleosomes in the promoter region of the stable MMTV template. These findings suggest novel CREB-independent, chromatin-dependent pathways for transcriptional regulation by cAMP.
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PMID:Chromatin-dependent regulation of the MMTV promoter by cAMP signaling is mediated through distinct pathways. 1283 91

Transforming growth factor-beta (TGF-beta) plays complex roles in carcinogenesis, as it may exert both tumor suppressor and pro-oncogenic activities depending on the stage of the tumor. SMAD proteins transduce signals from the TGF-beta receptors to regulate the transcription of specific target genes. Crosstalks with other signaling pathways may contribute to the specificity of TGF-beta effects. In this report, we have investigated the effects of cyclic adenosine 3',5'-monophosphate (cAMP), a key second messenger in the cellular response to various hormones, on SMAD-dependent signaling in human HaCaT keratinocytes. Using either an artificial SMAD3/4-dependent reporter construct or the natural TGF-beta target, plasminogen activator inhibitor-1, we show that membrane-permeable dibutyryl cAMP, and other intracellular cAMP-elevating agents such as the phosphodiesterase inhibitor isobutyl-methylxanthine, the adenylate cyclase activator forskolin, or exogenous prostaglandin E2 (PGE2), interfere with TGF-beta-induced SMAD-specific gene transactivation. Inhibition of protein kinase A (PKA), the main downstream effector of cAMP, with H-89, suppressed cAMP-dependent repression of SMAD-driven gene expression. Inversely, coexpression of either an active PKA catalytic subunit or that of the cAMP response element (CRE)-binding protein (CREB) blocked SMAD-driven gene transactivation. cAMP-elevating agents did not inhibit nuclear translocation and DNA binding of SMAD3/4 complexes, but abolished the interactions of SMAD3 with the transcription coactivators CREB-binding protein (CBP) and p300 in a PKA-dependent manner. These results suggest that suppression of TGF-beta/SMAD signaling and resulting gene transactivation by cAMP-inducing agents occurs via PKA-dependent, CREB-mediated, disruption of SMAD-CBP/p300 complexes.
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PMID:Cyclic adenosine 3',5'-monophosphate-elevating agents inhibit transforming growth factor-beta-induced SMAD3/4-dependent transcription via a protein kinase A-dependent mechanism. 1465 84


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