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)

Surfactant protein-A (SP-A) gene expression is developmentally regulated in fetal lung type II cells and is enhanced by cAMP. cAMP stimulation of SP-A gene expression is mediated by protein kinase A (PKA) phosphorylation of thyroid transcription factor 1 (TTF-1), expressed selectively in developing lung epithelium. In this study, we analyzed roles of CREB-binding protein (CBP) and steroid receptor coactivator-1 (SRC-1) in TTF-1 regulation of SP-A expression. Upon differentiation of human fetal lung in culture, nuclear localization of CBP, SRC-1, and TTF-1 increased in ductular epithelium in association with type II cell differentiation and induction of SP-A expression. In transient transfections, CBP and SRC-1 acted synergistically with TTF-1 to increase SP-A promoter activity. Overexpression of PKA catalytic subunit enhanced hSP-A promoter activation by SRC-1 plus TTF-1. Adenoviral E1A overexpression reduced TTF-1 +/- SRC-1 induction of SP-A promoter activity, suggesting a role of endogenous CBP/p300. TTF-1 interacted with SRC-1 and CBP in vitro. SRC-1 immunodepletion from type II cell nuclear extracts reduced binding to the TTF-1 binding element upstream of SP-A gene. In cultured type II cells, cAMP increased TTF-1 acetylation. This suggests that cAMP-mediated TTF-1 phosphorylation facilitates interaction with CBP and SRC-1, resulting in its hyperacetylation, further enhancing TTF-1 DNA-binding and transcriptional activity.
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PMID:Role of CBP/p300 and SRC-1 in transcriptional regulation of the pulmonary surfactant protein-A (SP-A) gene by thyroid transcription factor-1 (TTF-1). 1171 56

Signal transduction through cAMP to activate gene expression via the cAMP-responsive element (CRE) is one of the most intensively studied transcription pathways. In this pathway, transcription factor CRE-binding protein (CREB) recognizes the CRE enhancer on DNA. The CREB protein is activated via phosphorylation at serine 133 by protein kinase A and then is able to recruit coactivator CREB-binding protein (CBP) and its homologue p300. This recruitment of CBP/p300 is required for transcription activation. The mechanism for CBP/p300 to participate in this transcription process is still unclear. CBP and p300 are histone acetyltransferases (HAT) and able to associate with other HAT proteins. It has been reported that the regulation of nuclear receptor-mediated transcription initiation by p300 requires chromatin and its HAT function. The data shown here indicate that the requirements for chromatin and p300 HAT activity also apply to the activation of CREB-mediated transcription. Serine 133-phosphorylated CREB recruits p300 onto chromatin for efficient acetylation of nucleosomes. This targeted acetylation by p300 is essential to CREB-dependent transcription pathway.
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PMID:Histone acetylation by p300 is involved in CREB-mediated transcription on chromatin. 1175 10

Heterogeneous nuclear ribonucleoprotein D (hnRNP D) is implicated in transcriptional regulation. Alternative splicing of exons 2 and 7 generates four isoforms of the protein. We report here that only isoforms that contain the product of exon 2 (amino acids 79-97) were able to transactivate. Moreover, the exon 2-encoded protein domain alone was sufficient to drive transcription. TATA-binding protein and p300 interacted with a synthetic peptide corresponding to exon 2, and both proteins co-precipitated with hnRNP D. Stimulation of protein kinase A (PKA) and protein kinase C (PKC) synergistically induced the transactivating ability of hnRNP D, and the exon 2-encoded domain was sufficient for this inducibility. In kinase assays PKA phosphorylated Ser-87 of hnRNP D, whereas glycogen synthase kinase-3 beta (GSK-3 beta) phosphorylated Ser-83, but only if Ser-87 had been pre-phosphorylated by PKA. Phosphorylation of Ser-87 enhanced, whereas phosphorylation of Ser-83 repressed, transactivation. Overexpression of GSK-3 beta inhibited transactivation by hnRNP D, but stimulation of PKC negated the inhibitory effect of GSK-3 beta. We suggest that a hierarchical phosphorylation pathway regulates the transactivating ability of hnRNP D: PKA activates hnRNP D, but at the same time renders it sensitive to inhibition by GSK-3 beta; the latter inhibition can be suspended by inactivating GSK-3 beta with PKC.
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PMID:Protein kinase A enhances, whereas glycogen synthase kinase-3 beta inhibits, the activity of the exon 2-encoded transactivator domain of heterogeneous nuclear ribonucleoprotein D in a hierarchical fashion. 1190 55

Steroidogenic factor-1 (SF-1) is a member of the nuclear receptor superfamily that plays essential roles in the development of endocrine organs. Steroid receptor coactivator 1 and transcription intermediary factor 2 (TIF2) belong to the p160 coactivator family that mediates transcriptional activation by several nuclear receptors, including SF-1. Here, it is reported that another of the p160 coactivators, p/CIP, interacts with SF-1 through the activation function-2 domain. Both p300/CBP/cointegrator-associated protein (p/CIP) and TIF2 potentiated SF-1-mediated transcription from two reporter gene constructs in transfected nonsteroidogenic COS-1 cells and in adrenocortical Y1 cells. PKA was shown to stimulate SF-1 transcriptional activity, and coexpression of p/CIP together with the PKA catalytic subunit stimulated SF-1-mediated transactivation even further. In contrast, PKA catalytic subunit overexpression impaired the ability of TIF2 to potentiate SF-1-dependent transcription. Activation of PKA also inhibited the TIF2-mediated coactivation of other nuclear receptors such as PPAR alpha/-gamma and liver X receptor-alpha. The TIF2 mRNA levels were not affected by PKA, but instead we found that PKA activation led to a decrease in the levels of TIF2 protein. Moreover, the C-terminal activation domain 2 of TIF2 was required for the inhibitory effect of PKA, suggesting that this region is the target for the PKA-mediated down-regulation. Thus, in contrast to the regulation of p/CIP and steroid receptor coactivator 1, we suggest that activation of PKA leads to selective down-regulation of TIF2 and subsequently repression of TIF2 coactivator function.
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PMID:The nuclear receptor coactivators p300/CBP/cointegrator-associated protein (p/CIP) and transcription intermediary factor 2 (TIF2) differentially regulate PKA-stimulated transcriptional activity of steroidogenic factor 1. 1192 73

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 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

The aryl hydrocarbon (Ah) receptor (AhR) is a member of the basic helix-loop-helix PER-ARNT-SIM (PAS) transcription factor family. Consistent with the notion that PAS proteins are biological sensors, AhR binding to Ah toxicants induces or represses transcription of a wide range of genes and results in a cascade of toxic responses. However, an endogenous role for AhR in development and homeostasis is supported by (1) the discovery of low affinity, endogenous ligands; (2) studies demonstrating a role for the receptor in development of liver and vascular systems, that were established using mice lacking AhR expression; and (3) the presence of functional dioxin-responsive elements in promoter regions of genes involved in cellular growth and differentiation. A large body of recent literature has implicated AhR in multiple signal transduction pathways. AhR is known to interact with signaling pathways that are mediated by estrogen receptor and other hormone receptors, hypoxia, nuclear factor kappaB, and retinoblastoma protein. In addition, AhR complexes may affect cellular signaling through interactions with various other regulatory and signaling proteins, including PAS heterodimerization partners (ARNT), chaperone and immunophilin-like proteins (e.g. HSP90, XAP2/ARA9/AIP, p23), protein kinases and phosphatases (e.g. tyrosine kinases, casein kinase 2, protein kinase C), and coactivators (e.g. SRC-1, RIP 140, CBP/p300). Here we summarize the types of molecular cross talk that have been identified between AhR and cell signaling pathways.
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PMID:A dynamic role for the Ah receptor in cell signaling? Insights from a diverse group of Ah receptor interacting proteins. 1248 7

CBP/p300 recruitment to enhancer-bound complexes is a key determinant in promoter activation by many transcription factors. We present a novel mechanism of activating such complexes and show that pre-assembled Elk-1-p300 complexes become activated following Elk-1 phosphorylation by changes in Elk-1-p300 interactions rather than recruitment. It is known that Elk-1 binds to promoter in the absence of stimuli. However, it is unclear how activation of Elk-1 by mitogen-acivated protein kinase (MAPK)-mediated phosphorylation leads to targeted gene transactivation. We show that Elk-1 can interact with p300 in vitro and in vivo in the absence of a stimulus through the Elk-1 C-terminus and the p300 N-terminus. Phosphorylation on Ser383 and Ser389 of Elk-1 by MAPK enhances this basal binding but, most importantly, Elk-1 exhibits new interactions with p300. These interaction changes render a strong histone acetyltransferase activity in the Elk-1-associated complex that could play a critical role in chromatin remodeling and gene activation. The pre-assembly mechanism may greatly accelerate transcription activation, which is important in regulation of expression of immediate-early response genes, in particular those involved in stress responses.
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PMID:MAP kinase phosphorylation-dependent activation of Elk-1 leads to activation of the co-activator p300. 1251 34

The orphan nuclear receptor steroidogenic factor-1 (SF-1) plays pivotal roles in the development and function of steroidogenic organs. Here we describe the differential effect of protein kinase A (PKA) on coregulation of SF-1 dependent transcription by two p160 family members, p300/CBP co-integrator-associated protein (p/CIP) and transcription intermediary factor-2 (TIF2). Thus, whereas p/CIP-stimulated SF-1 dependent transcription is further potentiated by PKA, we show that activation of PKA leads to selective downregulation of TIF2 protein and a subsequent repression of TIF2 coactivator function. Using a yeast two-hybrid screen we also identified a novel zinc finger containing protein, which interacts with SF-1 via the AF-2 domain.
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PMID:Differential regulation of SF-1-cofactor interactions. 1253 Jun 55


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