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)

The transcript for the high-affinity Ca2+/calmodulin-binding protein calspermin is generated from the gene encoding Ca2+/calmodulin-dependent protein kinase IV only in postmeiotic germ cells during spermatogenesis. We demonstrate that this testis-specific calspermin transcript can be produced in heterologous cells by utilization of a promoter located in an intron of the calmodulin (CaM) kinase IV gene. Critical motifs within this promoter are two cyclic AMP response element (CRE)-like sequences located about -70 and -50 bp upstream of the transcriptional initiation site. Both CRE motifs are footprinted by the authentic testis-specific transcriptional activator CREM tau or by CREM tau present in adult testis nuclear extract. Whereas a 2.1-kb DNA fragment containing the calspermin promoter is inactive when transfected into NIH 3T3 cells, activity can be restored by cotransfection of CREM tau and protein kinase A or CaM kinase IV but not CaM kinase II alpha. Restoration of activity is greatly reduced by mutation of the two CRE motifs. Since CRE-like motifs have been identified in many genes uniquely expressed in postmeiotic germ cells, which contain abundant CREM tau protein, we suggest that CREM tau may function as one transcription factor responsible for the expression of postmeiotic germ cell-specific genes.
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PMID:Calspermin gene transcription is regulated by two cyclic AMP response elements contained in an alternative promoter in the calmodulin kinase IV gene. 779 65

cAMP response element-binding protein (CREB) and modulator protein (CREM) regulate the transcription of cAMP-responsive genes via phosphorylation by cAMP-dependent protein kinase A. Reverse transcription and polymerase chain amplification of RNA from male germ cells identify an alternatively spliced CREM isoform, CREM delta C-G, lacking four exons including those encoding the protein kinase A-regulated phosphorylation domain and the flanking glutamine-rich transcriptional activation domains. CREM delta C-G retains exons that encode the basic-leucine zipper (bZIP) DNA-binding domain, binds to cAMP response elements (CREs), and competitively inhibits binding of CREB and CREM to CREs. Expression of CREM delta C-G inhibits transcription of a CRE-containing chloramphenicol acetyltransferase reporter plasmid induced by endogenous CREB. Antiserum to CREM detects CREM delta C-G in elongated spermatids from rat testis. These observations indicate that CREM delta C-G is a unique form of a competitive negative regulator of CREB-mediated gene transcription expressed in a maturation-dependent manner in haploid germ cells. The developmental specificity of CREM delta C-G suggests that it may play a role in transcriptional regulation during spermatogenesis.
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PMID:An isoform of transcription factor CREM expressed during spermatogenesis lacks the phosphorylation domain and represses cAMP-induced transcription. 780 53

Transition protein 1 (TP1) is a small basic chromosomal protein that appears in mammalian spermatids during the period of chromatin condensation. The gene for TP1 from several species contains an apparent cAMP response element (CRE) in the immediate 5'-flanking region. The recent identification of high expression of the novel CRE-activating protein (CREM tau) in advanced testicular germ cells provided a stimulus to ask whether or not the TP1 CRE is functional. To this end we show both by gel retardation and by footprint assays that TP1 CRE forms specific bound complexes with proteins in whole testis nuclear extracts and that these complexes involve CREM as evidenced by recognition by a specific antibody. In addition, the TP1 CRE forms specific bound complexes with bacterially expressed CREM tau. Finally, the TPI CRE conveys protein kinase A-dependent induction to a linked chloramphenicol acetyl transferase gene when transfected into JEG-3 cells. Accordingly, TP1 is a good candidate for a testis-specific gene subject to CREM tau regulation.
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PMID:Identification of a functional cyclic adenosine 3',5'-monophosphate response element in the 5'-flanking region of the gene for transition protein 1 (TP1), a basic chromosomal protein of mammalian spermatids. 788 12

cAMP regulates the expression of a number of genes through the protein kinase A-mediated phosphorylation of CREB at Ser-133. The effects of Ser-133 phosphorylation appear to be primarily transmitted through a modulatory kinase-inducible domain in CREB that functions cooperatively with a 120-amino acid glutamine-rich region (Q2) to stimulate transcription. Indeed, the kinase-inducible domain activity alone is not sufficient to sustain a transcriptional response as illustrated by the CREM family of repressors, which contain the kinase-inducible domain but lack the Q2 region. Here we demonstrate that Q2 functions as a potent constitutive activator in vitro. The transcription factor TFIID fraction supports transcriptional activation by Q2, although the "TATA" binding protein alone does not, suggesting that other components of the TFIID complex mediate the response to CREB Q2. In fact, Q2 associates with the TATA binding protein-associated factor dTAFII110. As the transcriptionally inactive CREM alpha and beta proteins lack sequences in Q2 that are necessary for binding dTAFII110, our results suggest that these proteins may repress transcription because they are unable to interact with the basal transcription complex.
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PMID:The cAMP-regulated transcription factor CREB interacts with a component of the TFIID complex. 790 13

The cAMP-responsive element (CRE) modulator protein CREM alpha has been proposed to be a negative regulator of the CRE-binding protein (CREB). Precisely how CREM alpha inhibits CREB function is unclear, however. CREM alpha and CREB have highly related structures, and both proteins bind to consensus CRE sequences with similar affinities. Furthermore, both proteins can be phosphorylated by cAMP-dependent protein kinase A (PKA). Two models have been proposed to explain how CREM alpha could prevent the activation of genes by PKA-phosphorylated CREB: inhibitory CREM alpha homodimers could prevent occupancy of the CRE by CREB, or CREM alpha could block gene activation by forming non-functional CREB.CREM alpha heterodimers. To determine whether CREB-CREM alpha heterodimers are indeed non-functional, we engineered the leucine zipper regions of the two proteins to direct the pattern of dimerization. We then tested the biological activities of the phosphorylated and nonphosphorylated complexes in in vivo transcription assays. Our results indicate that CREM alpha can contribute to PKA-mediated gene activation when selectively heterodimerized with CREB. Furthermore, this transcriptional activity depends upon the ability of the complexes to be phosphorylated by PKA.
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PMID:Modulatory function of CREB.CREM alpha heterodimers depends upon CREM alpha phosphorylation. 796 42

Hormonally induced increases in cyclic AMP levels induce phosphorylation of the transcription factor CREB at a serine residue at position 133 by protein kinase A (ref. 1), enhancing its ability to activate transcription without affecting its intracellular location or DNA-binding activity. This effect is dependent on a 60-amino-acid region of CREB that contains Ser133 and is termed the kinase-inducible domain (KID)2, which also occurs in the CREB-related CREM-alpha and -beta proteins, although these are transcriptional repressors. Here we show that the KID domain confers a cAMP-inducible increase on the activity of the Q2 activation domain from CREB and the acidic activation domains from the yeast proteins GAL4 and GCN4. Remarkably, it retains this ability even when attached to a separate polypeptide bound to an adjacent site in the promoter. KID may therefore be the first of a new class of conditional activators that work through other promoter-bound factors to stimulate gene expression in response to hormonal stimuli.
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PMID:Protein-kinase-A-dependent activator in transcription factor CREB reveals new role for CREM repressors. 810 91

The cyclic AMP-response element (CRE), a transcriptional enhancer, is regulated by CREB (CRE-binding protein) which is the leucine zipper protein phosphorylated by protein kinase A in response to cAMP signal. The highly homologous protein CREM (CRE-modulator) is thought to modulate CREB-stimulated transcription, and is also involved in transcriptional control during spermatogenesis. In this paper, we report two types of cDNAs of human CREM (hCREM), type 1 and type 2; type 1 is a group of human counterparts of the mouse CREM alpha and type 2 is a novel form having a distinct 5' exon which is unrelated to any species of the CREB and CREM isoforms so far described. This unique 5' region of type 2 hCREM may suggest its independent expression from type 1 CREM. The specific 5' region of type 2 hCREM consisted of 88 bp, containing an initiation codon for translation, but no possible phosphorylation site, suggesting different roles from type 1 CREM. Both type 1 and 2 hCREMs are expressed in lymphoid and non-lymphoid cell lines. Their excess expression by transfection induced suppression of cAMP-mediated activation of transcription, suggesting their negative regulation of CRE-mediated transcription.
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PMID:Novel isoforms of human cyclic AMP-responsive element modulator (hCREM) mRNA. 820 79

Phosphorylation is one of the major mechanisms by which the activity of transcription factors can be regulated. We have investigated the role of phosphorylation in the regulation of the transcription factor CREM. We show that the CREM tau activator is phosphorylated on multiple serine and threonine residues in vivo. Stimulation of various signal transduction pathways by forskolin, TPA or Ca2+ ionophore leads to enhanced phosphorylation of serine 117, concomitant with an increase in the transactivation potential of CREM tau. We have identified multiple kinases that can also phosphorylate S117 in vitro. Moreover, we show that casein kinase I and II cooperatively phosphorylate CREM tau on multiple residues, eliciting enhanced DNA binding. Cooperative phosphorylation is also observed with other kinases. These results show that the activity of CREM tau is regulated by multiple phosphorylation events, suggesting that CREM could be considered as a nuclear effector where signalling pathways may converge and/or cross-talk.
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PMID:Multiple and cooperative phosphorylation events regulate the CREM activator function. 840 58

The pp70/85-kDa S6 kinases, collectively referred to as pp70S6k, are thought to participate in transit through the G1 phase of the cell cycle. pp70S6k regulates the phosphorylation of the 40S ribosomal protein S6 and the transcription factor CREM tau. pp70S6k is regulated by serine/threonine phosphorylation, and although 1-phosphatidylinositol 3-kinase and phospholipase C have been implicated as upstream regulators, the mechanism of activation and identity of the upstream pp70S6k kinases remain unknown. To improve our understanding of how this mitogen-stimulated protein kinase is regulated by growth factors and the immunosuppressant rapamycin, we have initiated a structure/function analysis of pp70S6k. Our results indicate that both the N and C termini participate in the complex regulation of pp70S6k activity.
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PMID:Structural and functional analysis of pp70S6k. 852 31

Nuclear proteins of the human peripheral blood T lymphocytes that bind to the CREs located within three 21-bp repeat enhancers of the HTLV-I promoter belong to the CREB/CREM family of bZIP transcription factors. It has been shown previously that Tax enhances transactivation of these CREs by direct interactions with the bZIP domain of the transcription factors to stabilize DNA-binding. We show that CREB and CREM bind all three CRE sequences of the HTLV-I promoter which are important determinants in Tax-elicited transactivation as well as PKA-mediated activation of the HTLV-I promoter. Tax and PKA activate transcription from a HTLV-I-LTR CAT reporter plasmid transfected to NIH 3T3 cells, and CREM attenuates the activation. In the context of a GAL4 CREB fusion protein in which the DNA-binding bZIP domain of CREB is replaced by GAL4 binding domain, a single amino acid substitution of serine-133, phosphorylated by PKA and critical for the transactivation function of CREB, attenuates both Tax and PKA-mediated transcriptional responses. These observations suggest that Tax enhances CREB-mediated transactivation of the HTLV-I promoter by a mechanism apart from, and/or in addition to, the reported stabilization of DNA-binding by interaction with the bZIP domain of CREB.
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PMID:Modulation of Tax and PKA-mediated expression of HTLV-I promoter via cAMP response element binding and modulator proteins CREB and CREM. 854 66


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