Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.1 (protein kinase)
 81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Protein phosphorylation catalyzed by the cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA) is implicated in regulating zygotic gene activation in the two-cell mouse embryo (Poueymirou and Schultz; Dev Biol 133:588-599, 1989). We now provide evidence that H8, which is a PKA inhibitor, inhibits expression of an hsp70-driven beta-galactosidase reporter gene and that the concentration-dependence of this inhibition is similar to that for inhibiting expression of a stage-specific gene(s) that is a product of zygotic gene activation. We also demonstrate that neither cAMP nor serum can stimulate the expression, as detected by a histochemical assay, of a cAMP response element (CRE)- or serum response element (SRE)-driven beta-galactosidase reporter gene, respectively, in either germinal vesicle-intact oocytes or aphidicolin-arrested one-cell embryos that are chronologically at the tw-cell stage. In contrast, although 12-O-tetradecanoyl phorbol-13-acetate (TPA) does not stimulate expression of a TPA response element (TRE)-driven beta-galactosidase reporter gene in germinal vesicle-intact oocytes, it stimulates such expression in aphidicolin-arrested one-cell embryos. Moreover, TPA can stimulate the expression of either a CRE- or an SRE-driven beta-galactosidase reporter gene in such embryos. Results of these studies further implicate protein phosphorylation in regulating zygotic gene activation, along with its role in modulating enhancer function in the early mouse embryo.
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PMID:Zygotic gene activation in the mouse embryo: involvement of cyclic adenosine monophosphate-dependent protein kinase and appearance of an AP-1-like activity. 132 5

Perturbing the changes in protein phosphorylation accompanying the first cleavage can inhibit the appearance of a set of proteins whose synthesis is inhibited by alpha-amanitin (transcription-requiring proteins, TRPs) (W. T. Poueymirou and R. M. Schultz, 1987, Dev. Biol. 121, 489-498); synthesis of the TRPs is likely to represent activation of transcription of the embryonic genome that occurs at the 2-cell stage during mouse development. In the present study, we report the effects of three different inhibitors of the cAMP-dependent protein kinase, N-[2-(methylamino)ethyl]-5-isoquinoline-sulfonamide (H8), (Rp)-cAMPs, and protein kinase inhibitor (PKI), each of which inhibits the kinase by a different mechanism, on cleavage of 2-cell embryos and synthesis of the TRPs. Two-cell embryos possess PK-A activity, which is inhibited by each of these inhibitors. Both H8 and (Rp)-cAMPs inhibit cleavage of 2-cell embryos in a concentration-dependent manner; similar concentrations of H7, which is a less potent inhibitor of PK-A, do not inhibit cleavage. H8 and (Rp)-cAMPS inhibit in a concentration-dependent manner TRP synthesis, whereas higher concentrations of H7 are required to inhibit TRP synthesis. Microinjected PKI also inhibits synthesis of the TRPs. In addition, H8 inhibits the accumulation of translatable messenger RNAs that are likely to encode for the TRPs. Last, H8, but not H7, inhibits the phosphorylation of a phosphoprotein in 2-cell embryos. Results of these studies suggest a role for protein phosphorylation catalyzed by cAMP-dependent protein kinase in regulating transcription in the early mouse embryo.
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PMID:Regulation of mouse preimplantation development: inhibition of synthesis of proteins in the two-cell embryo that require transcription by inhibitors of cAMP-dependent protein kinase. 254 2

Elevating cAMP levels in mouse blastocysts increases the rate of blastocoel expansion (F. Manejwala, E. Kaji, and R. M. Schultz, 1986, Cell, 46, 95-103), which requires extracellular sodium (F. Manejwala, E. J. Crago, Jr., and R. M. Schultz, 1989, Dev. Biol. 133, 210-220). We report that cAMP analogs that can activate the cAMP-dependent protein kinase stimulate 22Na+ uptake by cavitating mouse blastocysts and that inhibitors of cAMP-dependent protein kinase activity inhibit the cAMP-stimulated increase in both the rate of blastocoel expansion and 22Na+ uptake.
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PMID:Blastocoel expansion in the preimplantation mouse embryo: stimulation of sodium uptake by cAMP and possible involvement of cAMP-dependent protein kinase. 255 38

A cDNA clone for the membrane form of guanylate cyclase has been isolated from the testis of the sea urchin Strongylocentrotus purpuratus. An open reading frame predicts a protein of 1125 amino acids including an apparent signal peptide of 21 residues; a single transmembrane domain of 25 amino acids divided the mature protein into an amino-terminal, extracellular domain of 485 amino acids and a carboxyl domain of 594 intracellular amino acids. Three potential Asn-linked glycosylation sites were present in the proposed extracellular domain. The deduced protein sequence was homologous to the protein kinase family and contained limited but significant regions of identity with a low molecular weight atrial natriuretic peptide receptor. The carboxyl region (202 amino acids) was 42% identical with a subunit of the cytoplasmic form of guanylate cyclase recently cloned from bovine lung (Koesling, D., Herz, J., Gausepohl, H., Niroomand, F., Hinsch, K.-D., Mulsch, A., Bohme, E., Schultz, G., and Frank, R. (1988) FEBS Lett. 239, 29-34). Therefore, the membrane form of guanylate cyclase is a member of an apparently large family of proteins that includes the low molecular weight atrial natriuretic peptide receptor, the soluble form of guanylate cyclase and protein kinases.
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PMID:The membrane form of guanylate cyclase. Homology with a subunit of the cytoplasmic form of the enzyme. 256 49

Invasive and metastatic cells require protease expression for migration through the extracellular matrix. Metastatic NIH 3T3 fibroblasts transformed by different activated ras genes showed two different protease phenotypes, rasuPA+/CL- and rasCL+/uPA- (Zhang, J-Y., and Schultz, R. M. (1992) Cancer Research 52, 6682-6689). Phenotype rasuPA+/CL- is dependent on expression of the serine-type protease urokinase plasminogen activator (uPA) and the phenotype rasCL+/uPA- on the cystine-type protease cathepsin L (CL) for lung colonization in experimental metastasis. The existence of multiple invasive phenotypes on ras-isoform transformation implied the activation of alternative pathways downstream from Ras. We now show that c-Raf-1, extracellular signal-regulated protein kinase (ERK)-1, and ERK-2 are hyperphosphorylated, and the ERK activity is high in both the uPA- and CL-dependent ras-transformed invasive phenotypes. Levels of c-Jun and c-Jun NH2-terminal kinase (JNK) activity are also high in the uPA-dependent phenotype, but they are almost undetectable in the CL-dependent phenotype. The uPA Ras-response element is a PEA3/URTF element, and mobility shift assays show a strong PEA3/URTF protein band in the uPA-dependent phenotype. This band is competed by a consensus AP-1 DNA sequence and by antibodies to PEA3 and c-Jun. Thus, the uPA-invasive phenotype appears to require the activation of Ets/PEA3 and c-Jun transcription factors activated by the ERK and JNK pathways, while the CL-invasive phenotype appears to require ERK activity with suppression of JNK and c-Jun activities. These postulates are supported by the introduction of a dominant negative c-Jun, TAM67, into cells of phenotype rasuPA+/CL-, which down-regulated the high uPA mRNA levels characteristic of this phenotype to basal levels and up-regulated basal levels of CL mRNA to levels similar to those observed in cells of phenotype rasCL+/uPA-. We conclude that the JNK pathway acts as a switch between two distinct protease phenotypes that are redundant in their abilities to grow tumors and metastasize.
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PMID:Characterization of downstream Ras signals that induce alternative protease-dependent invasive phenotypes. 903 12