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)

Id is a helix-loop-helix protein which forms heterodimer with ubiquitous and/or tissue-specific basic helix-loop-helix proteins and inhibits their DNA binding. It has been noted that putative phosphorylation sites for various protein kinases exist in rat Id1, Id2 and Id3. We show here that Id1 and Id2 can be phosphorylated in vitro by cAMP-dependent protein kinase, Id2 and Id3 by cdc2 kinase, and all three Ids by protein kinase C. The phosphorylated Id1 was actually immunoprecipitated in nerve-growth-factor-stimulated PC12 cells. Gel mobility shift assays, however, demonstrated that neither phosphorylation of Id proteins by cAMP-dependent protein kinase nor phosphorylation of E47 by protein kinase C affected the inhibition of E47 homodimer formation and its DNA binding. Taken together with other observations, phosphorylation of Id proteins may play a role in regulation of cell differentiation but not directly in the dimerization and DNA binding.
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PMID:Phosphorylation of helix-loop-helix proteins ID1, ID2 and ID3. 786 97

The recent identification of Max, a nuclear phosphoprotein that dimerizes with members of the Myc protein family, has provided an additional tool to examine the role of the Myc oncoprotein as a sequence-specific DNA binding protein and a potential regulator of gene transcription. Here we report the nucleotide sequence of an avian max gene isolated from a lambda EMBL3 genomic library prepared from size-selected chicken embryo fibroblast DNA. The complete transcription unit encoding chicken Max is contained on a 5.7 kbp BglII DNA fragment which expresses an appropriately sized max mRNA of 1.5 kb following transfection of C3H10T1/2 mouse fibroblasts. The coding region of the chicken max gene is organized into five exons and the overall identity between the human and chicken max coding sequences is 85% at the nucleotide level and 96% at the amino acid level. The basic helix-loop-helix/leucine zipper region, the casein kinase II phosphorylation sites and the nuclear localization signal sequence are 100% conserved in all vertebrate Max proteins characterized to date. DNA sequence analysis of the 5' flanking region of the chicken max coding sequence reveals the absence of consensus TATA or CAAT motifs, but the presence of numerous GC-rich sequences that are typical in eukaryotic genes which are expressed constitutively in different tissues and under different growth conditions.
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PMID:Structural analysis of the chicken max gene. 829 Feb 77

Myf-5 and MyoD are members of a family of muscle-specific basic helix-loop-helix (bHLH) proteins that are fundamental for myogenic cell differentiation and transcriptional activation of muscle-specific genes. Here we report that elevated levels of the intracellular signaling molecule cAMP and overexpression of cAMP-dependent protein kinase (PKA) inhibit myogenic differentiation. PKA represses the transcriptional activation of muscle-specific genes by the myogenic regulators Myf-5 and MyoD. The repression is directed at the basic HLH domain and is mediated through the E-box DNA consensus motif to which these proteins bind. However, phosphorylation of Myf-5 and MyoD by PKA in vitro does not affect their ability to bind to DNA. PKA specifically inhibits the activity of myogenic bHLH proteins, but not of other HLH proteins, such as the ubiquitously expressed E2A gene products E12 and E47 (E2-5). Our results demonstrate that PKA mediates the cAMP-induced inhibition of muscle cell differentiation by repressing the activity of Myf-5 and MyoD. The inhibition by PKA occurs post-translationally and presumably affects the transactivation process at a step following DNA-binding. The regulation of Myf-5 and MyoD function by a cAMP-dependent pathway may partly explain how external signals generated by serum and certain peptide growth factors can be transduced to the nucleus and inhibit dominant-acting factors that are responsible for myoblast differentiation.
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PMID:cAMP-dependent protein kinase represses myogenic differentiation and the activity of the muscle-specific helix-loop-helix transcription factors Myf-5 and MyoD. 838 7

Neural-specific expression of the mouse regulatory type-I beta (RI beta) subunit gene of cAMP-dependent protein kinase is controlled by a fragment of genomic DNA comprised of a TATA-less promoter flanked by 1.5 kilobases of 5'-upstream sequence and a 1.8-kilobase intron. This DNA contains a complex arrangement of transcription factor binding motifs, and previous experiments have shown that many of these are recognized by proteins found in brain nuclear extract. To identify sequences critical for RI beta expression in functional neurons, we performed a deletion analysis in transgenic mice. Evidence is presented that the GC-rich proximal promoter is responsible for cell type-specific expression in vivo because RI beta DNA containing as little as 17 base pairs (bp) of 5'-upstream sequence was functional in mouse brain. One likely regulatory element coincides with the start of transcription and includes an EGR-1 motif and 3 consecutive SP1 sites within a 21-bp interval. Maximal RI beta promoter activity required the adjacent 663 bp of 5'-upstream DNA where most, but not all, of the regulatory activity was localized between position -663 and -333. A 37-bp direct repeat lies within this region that contains 2 basic helix-loop-helix binding sites, each of which are overlapped by two steroid hormone receptor half-sites, and a shared AP1 consensus sequence. Intron I sequences were also tested, and deletion of a 388-bp region containing numerous Sp1-like sequences lowered transgene activity significantly. These results have identified specific regions of the RI beta promoter that are required for the expression of this signal transduction protein in mouse neurons.
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PMID:Promoter sequences in the RI beta subunit gene of cAMP-dependent protein kinase required for transgene expression in mouse brain. 857 64

The myogenic regulatory factors (MRFs) are a subclass of a much larger group of basic helix-loop-helix transcription factors which includes members of the E protein such as E47, E2-2, and HEB. Although the MRFs are unique in their ability to confer a myogenic phenotype on nonmuscle cells, they require E protein partners to form a MRF-E protein heterodimer, which represents the functional myogenesis-inducing complex. The mechanisms controlling homodimer and heterodimer formation in vivo remain largely unknown, although it is likely that posttranslational modification of one or both basic helix-loop-helix partners is critical to this regulatory event. In this respect, MyoD and MRF4, both members of the MRF family, exist in vivo as phosphoproteins and contains multiple consensus phosphorylation sites, including sites for casein kinase II (CKII) phosphorylation. In this study, we demonstrate that overexpression of CKII increases the transcriptional activities of MRF4 and MyoD in vivo. Interestingly, mutation of the individual CKII sites within MRF4 and MyoF does not alter the ability of CKII to enhance MRF transcriptional activity, suggesting that the effect of CKII expression on the MRFs is indirect. Given that the MRFs require dimerization with E protein partners to activate muscle-specific transcription, the effects of CKII expression on E protein function also were examined. Our studies show that E47 serves as an in vitro substrate for CKII and that CKII-phosphorylated E-47 proteins no longer bind to DNA. These observations were confirmed by in vivo experiments showing that overexpressing of CKII produces a dramatic reduction in E47 homodimer-directed transcription. We conclude from these studies that CKII may act as a positive regulator of myogenesis by preventing E protein homodimers from binding to muscle gene regulatory elements.
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PMID:Casein kinase II increases the transcriptional activities of MRF4 and MyoD independently of their direct phosphorylation. 865 35

Ectopic activation of the TAL-1 gene in T lymphocytes occurs in the majority of cases of human T cell acute lymphoblastic leukemia (T-ALL), yet experiments to date have failed to demonstrate a direct transforming capability for tal-1. The tal-1 gene product is a serine phosphoprotein and basic helix-loop-helix (bHLH) transcription factor known to regulate embryonic hematopoiesis. We have established a transgenic mouse model in which tal-1 mis-expression in the thymus results in the development of clonal T cell lymphoblastic leukemia/lymphoma. Thus, overexpression of tal-1 alone can be transforming, verifying its pathogenic role in human T-ALL. In addition, leukemogenesis is accelerated dramatically by transgenic co-expression of tal-1 and the catalytic subunit of casein kinase IIalpha (CKIIalpha), a serine/threonine protein kinase known to modulate the activity of other bHLH transcription factors. Although tal-1 is a substrate for CKII, the synergy of the tal-1 and CKIIalpha transgenes appears to be indirect, perhaps mediated through the E protein heterodimeric partners of tal-1. These studies prove that dysregulated tal-1 is oncogenic, providing a direct molecular explanation for the malignancies associated with TAL-1 activation in human T-ALL.
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PMID:Tal-1 induces T cell acute lymphoblastic leukemia accelerated by casein kinase IIalpha. 889 60

Activation of cyclic AMP-dependent protein kinases (protein kinase A, PKA) by gonadotropins and cyclic AMP (cAMP) plays an important role in the regulation of testicular functions. A regulatory subunit, RIIbeta, of PKA is transcriptionally induced in rat Sertoli cells in response to treatment with cAMP. The present study addresses regulatory mechanisms leading to increased transcription of the rat RIIbeta gene. We have localized a footprint which overlaps one of the major transcription initiation sites in the basal promoter (-293 to -123). One of the proteins binding this sequence belongs to the NF-1 family of transcription factors. We also observed binding to a basic helix-loop-helix (bHLH) response element. Furthermore, transfection studies of various 5'-deletions of the rat RIIbeta gene in primary cultures of rat Sertoli cells and in peritubular cells revealed the presence of an upstream region (-723 to -395, cAMP-responsive region) inhibiting basal expression from the rat RIIbeta gene only in Sertoli cells. This region was found to enhance cAMP responsiveness in Sertoli cells but not in peritubular cells. Interactions with downstream elements seemed to be important for the function of the cAMP-responsive region. Although some short stretches reveal homology to the cAMP-responsive regions of other slowly cAMP-responding genes, and an AP-1-like element is present, no strong resemblance to any known regulatory element responsive to cAMP is found.
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PMID:Characterization of the 5'-flanking region of the gene for the cAMP-inducible protein kinase A subunit, RIIbeta, in Sertoli cells. 917 34

The ability of basic helix-loop-helix muscle regulatory factors (MRFs), such as MyoD, to convert nonmuscle cells to a myogenic lineage is regulated by numerous growth factor and oncoprotein signaling pathways. Previous studies have shown that H-Ras 12V inhibits differentiation to a skeletal muscle lineage by disrupting MRF function via a mechanism that is independent of the dimerization, DNA binding, and inherent transcriptional activation properties of the proteins. To investigate the intracellular signaling pathway(s) that mediates the inhibition of MRF-induced myogenesis by oncogenic Ras, we tested two transformation-defective H-Ras 12V effector domain variants for their ability to alter terminal differentiation. H-Ras 12V,35S retains the ability to activate the Raf/MEK/mitogen-activated protein (MAP) kinase cascade, whereas H-Ras 12V,40C is unable to interact directly with Raf-1 yet still influences other signaling intermediates, including Rac and Rho. Expression of each H-Ras 12V variant in C3H10T1/2 cells abrogates MyoD-induced activation of the complete myogenic program, suggesting that MAP kinase-dependent and -independent Ras signaling pathways individually block myogenesis in this model system. However, additional studies with constitutively activated Rac1 and RhoA proteins revealed no negative effects on MyoD-induced myogenesis. Similarly, treatment of Ras-inhibited myoblasts with the MEK1 inhibitor PD98059 revealed that elevated MAP kinase activity is not a significant contributor to the H-Ras 12V effect. These data suggest that an additional Ras pathway, distinct from the well-characterized MAP kinase and Rac/Rho pathways known to be important for the transforming function of activated Ras, is primarily responsible for the inhibition of myogenesis by H-Ras 12V.
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PMID:Signaling through mitogen-activated protein kinase and Rac/Rho does not duplicate the effects of activated Ras on skeletal myogenesis. 919 90

Zebrafish neurogenin1 encodes a basic helix-loop-helix protein which shares structural and functional characteristics with proneural genes of Drosophila melanogaster. neurogenin1 is expressed in the early neural plate in domains comprising more cells than the primary neurons known to develop from these regions and its expression is modulated by Delta/Notch signalling, suggesting that it is a target of lateral inhibition. Misexpression of neurogenin1 in the embryo results in development of ectopic neurons. Markers for different neuronal subtypes are not ectopically expressed in the same patterns in neurogenin1-injected embryos suggesting that the final identity of the ectopically induced neurons is modulated by local cues. Induction of ectopic motor neurons by neurogeninl requires coexpression of a dominant negative regulatory subunit of protein kinase A, an intracellular transducer of hedgehog signals. Moreover, the pattern of endogenous neurogenin1 expression in the neural plate is expanded in response to elevated levels of Hedgehog (Hh) signalling or abolished as a result of inhibition of Hh signalling. Together these data suggest that Hh signals regulate neurogenin1 expression and subsequently modulate the type of neurons produced by Neurogenin1 activity.
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PMID:The activity of neurogenin1 is controlled by local cues in the zebrafish embryo. 940 73

Protein kinase C (PKC)- and protein kinase A (PKA)-mediated modulation of the transactivation potential of human aryl hydrocarbon receptor nuclear translocator (hARNT), a basic helix-loop-helix (bHLH)-PAS transcription factor, and the bHLH-ZIP transcription factors USF-1 (for upstream regulatory factor 1) and c-Myc were examined. An 81 nM dose of the PKC activator phorbol-12-myristate-13-acetate (PMA), shown here to specifically activate PKC in COS-1 cells, or a 1 nM dose of the PKA activator 8-bromoadenosine-3',5'-cyclic monophosphate (8-Br-cAMP) results in 2. 6- and 1.9-fold enhancements, respectively, in hARNT-mediated transactivation of the class B, E-box-driven reporter pMyc3E1bLuc relative to identically transfected, carrier solvent-treated COS-1 cells. In contrast, 81 nM PMA and 1 nM 8-Br-cAMP did not enhance transactivation of pMyc3E1bLuc-driven by USF-1 and c-Myc expression relative to identically transfected, carrier-treated COS-1 cells. Co-transfection of pcDNA3/ARNT-474-Flag, expressing a hARNT carboxyl-terminal transactivation domain deletion, and pMyc3E1bLuc does not result in induction of reporter activity, suggesting PMA's effects do not involve formation of unknown hARNT-protein heterodimers. Additionally, PMA had no effect on hARNT expression relative to Me2SO-treated cells. Metabolic 32P labeling of hARNT in cells treated with carrier solvent or 81 nM PMA demonstrates that PMA does not increase the overall phosphorylation level of hARNT. These results demonstrate, for the first time, that the transactivation potential of ARNT in a dimer context can be specifically modulated by PKC or PKA stimulation and that the bHLH-PAS and bHLH-ZIP transcription factors are differentially regulated by these pathways in COS-1 cells.
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PMID:Protein kinase C modulates aryl hydrocarbon receptor nuclear translocator protein-mediated transactivation potential in a dimer context. 1021 12


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