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PubMed2004

snf1lk encodes a protein kinase that may function in cell cycle regulation.

msk, myocardial SNF1-like kinase, was originally isolated in a screen for kinases expressed during early cardiogenesis in the mouse. msk maps to the proximal end of mouse chromosome 17 in a region that is syntenic with human chromosome 21q22.3, where the gene for SNF1LK, a predicted protein that shares 80% identity at the amino acid level with Msk, is located. Accordingly, msk has been redesignated snf1lk. Interestingly, the region encompassing the SNF1LK locus has been implicated in congenital heart defects often observed in patients with Down syndrome. snf1lk is also expressed in skeletal muscle progenitor cells of the somite beginning at 9.5 dpc. These data suggest a more general role for snf1lk in the earliest stages of muscle growth and/or differentiation. Consistent with a role in cell cycling, we observe that Chinese hamster ovary cells that express a tetracycline-inducible SNF1LK kinase domain do not divide, but undergo additional rounds of replication to yield 8N and 16N cells. These data suggest a possible function for SNF1LK in G2/M regulation. We show data that indicate that SNF1LK does not share functional homology with other SNF1-related kinases, but represents a new subclass with novel molecular activities.

Amino Acid Sequence↗

PubMed1995

Activity of single-stranded DNA endonucleases in mung bean is associated with cell division.

A single-strand-specific endonuclease from mung bean sprouts is widely used in molecular biology. However, the biological role of this enzyme is unknown. We studied the spatial and temporal activity of single-stranded DNA endonucleases in mung bean seedling by following enzyme activity that linearizes supercoiled plasmid DNA, a characteristic of this type of enzyme. The formation of a linear molecule from supercoiled DNA was found to occur in two distinguishable steps. The first, which involves introducing a nick into the supercoiled DNA and relaxing it, is very rapid and complete within a few seconds. The second step of cleaving the opposite strand to generate a unit-length linear duplex DNA is a relatively slow process. Analysis of the DNA cleavage sites showed the nuclease preferentially cuts supercoiled DNA at an AT-rich region. Varying levels of nuclease activity could be detected in different tissues of the mung bean seedling. The highest activity was in the root tip and was correlated with histone H1 kinase activity. This implies a link between nuclease activity and cell division. Induction of cell division in mung bean hypocotyls with auxin promoted formation of root primordia and considerably increased the activity of single-stranded DNA endonucleases. The nuclease activity and histone H1 kinase activity were reduced in mung bean cuttings treated with hydroxyurea, but not in cuttings treated with oryzalin. The potential function of single-stranded DNA endonucleases is discussed.

Base Sequence↗

PubMed1988

ATP-gamma-S (adenosine 5'-O-(3-thiotriphosphate)) microinjection increases progesterone-stimulated histone kinase activity in Xenopus oocytes.

Progesterone stimulates the activity of a potent Ca2+- and cyclic nucleotide-independent histone kinase in Xenopus oocytes. Microinjection of ATP-gamma-S during the course of meiotic maturation or after the oocytes had arrested at second meiotic metaphase resulted in a further increase of this histone kinase activity in progesterone-stimulated oocytes. ATP-gamma-S microinjection also increased and stabilized the activity of the maturation-promoting factor. The possible mechanism of ATP-gamma-S action is discussed.

Adenosine Triphosphate↗

PubMed1975

Protein kinases in brown adipose tissue of developing rats. I. GTP as nucleotide substrate for histone phosphorylation.

100 000 times g soluble extracts from interscapular brown adipose tissue catalyzed the transfer of the terminal phosphoryl group from GTP to histone. Maximal velocity was achieved only with both cyclic AMP and ATP present. The cyclic AMP dose-response curve was the same as for the ATP-utilizing enzyme, with maximum stimulation at 0.5 muM. ATP (1--100muM) increased the rate of histone phosphorylation with GTP as the radioactive substrate. Higher concentrations had a dilution effect similar to that of GTP on the ATP-utilizing enzyme. Similar effects were observed with ADP and AMP. The apparent Km values for histone were the same with both GTP and ATP as nucleotide substrates. The effects of pH, purified beef muscle kinase inhibitor and of NaCl were also the same. Maximum velocities of histone phosphorylation from ATP and those from GTP were almost the same in brown fat of all age groups testes, Separated on histone-Sepharose, the GTP-utilizing activity was absolutely dependent on the re-addition of the ATP-utilizing enzyme (a linear relationship with a slope of approx. 0.95). An extremely active nucleotide phosphotransferase activity was found in the same subcellular fraction. The rate of equilibration of the gamma-32-P between GTP and ATP could account for all the histone phosphorylation with [gamma-32-P] GTP. It is concluded that, in spite of the presence of nucleotide phosphotransferase and ATP-protein kinase activities, a direct transfer from GTP to a protein substrate cannot be excluded. Also, histone may not be the natural protein acceptor for GTP-linked phosphorylation.

Adenine Nucleotides↗

PubMed1993

Cell cycle-regulated phosphorylation of the pre-mRNA-binding (heterogeneous nuclear ribonucleoprotein) C proteins.

Heterogeneous nuclear ribonucleoprotein (hnRNP) complexes, the structures that contain heterogeneous nuclear RNA and its associated proteins, constitute one of the most abundant components of the eukaryotic nucleus. hnRNPs appear to play important roles in the processing, and possibly also in the transport, of mRNA. hnRNP C proteins (C1, M(r) of 41,000; C2, M(r) of 43,000 [by sodium dodecyl sulfate-polyacrylamide gel electrophoresis]) are among the most abundant pre-mRNA-binding proteins, and they bind tenaciously to sequences relevant to pre-mRNA processing, including the polypyrimidine stretch of introns (when it is uridine rich). C proteins are found in the nucleus during the interphase, but during mitosis they disperse throughout the cell. They have been shown previously to be phosphorylated in vivo, and they can be phosphorylated in vitro by a casein kinase type II. We have identified and partially purified at least two additional C protein kinases. One of these, termed Cs kinase, caused a distinct mobility shift of C proteins on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. These phosphorylated C proteins, the Cs proteins, were the prevalent forms of C proteins during mitosis, and Cs kinase activity was also increased in extracts prepared from mitotic cells. Thus, hnRNP C proteins undergo cell cycle-dependent phosphorylation by a cell cycle-regulated protein kinase. Cs kinase activity appears to be distinct from the well-characterized mitosis-specific histone H1 kinase activity. Several additional hnRNP proteins are also phosphorylated during mitosis and are thus also potential substrates for Cs kinase. These novel phosphorylations may be important in regulating the assembly and disassembly of hnRNP complexes and in the function or cellular localization of RNA-binding proteins.

Adenosine Triphosphate↗

PubMed1980

H3-specific nucleohistone kinase of bovine thymus chromatin. Purification, characterization, and specificity for threonine residue 3.

Bovine thymus chromatin contains a cAMP-independent histone kinase which is entirely specific for a single site on H3 whether the histone substrate is soluble or associated with DNA in chromatin (Shoemaker, C. B., and Chalkley, R. (1978) J. Biol. Chem. 253, 5802--5807). The H3-kinase has been extracted, purified 2000-fold and extensively characterized. The purified enzyme produces a single band upon neutral gel electrophoresis and two distinct bands of 21,000 and 23,000 daltons upon sodium dodecyl sulfate-gel electrophoresis. Following subcellular fractionation, most or all of the enzymatic activity is associated with chromatin. Soluble histone inactivates H3-kinase after short incubations while a chromatin substrate permits the enzyme to remain active until H3 is fully phosphorylated. Assay conditions have been optimized in terms of pH and several cofactor concentrations. Optimal MgCl2 concentration occurs at 50 mM, while for MnCl2 the optimum is 300 microM. H3-kinase has a molecular weight of 38,000 as estimated by exclusion chromatography. The Km for ATP is 160 +/- 23 microM. The enzyme displays extraordinary substrate specificity for H3 histone as no other thymus protein has been observed as a substrate. Phosphorylation of H3 occurs at threonine residue 3.

Animals↗

PubMed1996

Alteration of cell cycle-dependent histone phosphorylations by okadaic acid. Induction of mitosis-specific H3 phosphorylation and chromatin condensation in mammalian interphase cells.

Effects of okadaic acid (OA), a protein phosphatase inhibitor, on chromatin structure and phosphorylation of histones were examined using HeLa and N18 cells. The chromatin condensation in HeLa cells was mild and resemble prometaphase nuclei, while the condensation in N18 cells was extensive and chromatin became a compact body. H2A in HeLa cells was extensively and consistently phosphorylated at the same site throughout the cell cycle, and H3 was demonstrated to be phosphorylated at the mitosis-specific site Ser10. In contrast, H1 phosphorylation was rapidly decreased in most sites within 3 h. The reduction of H1 phosphorylation was accompanied by a quantitative change in the set of H1 phosphopeptides. During the early phase of the OA treatment, H1 phosphorylation was transiently elevated in tandem, whereas H3 phosphorylation reached a maximum somewhat later. The results suggest that mitosis-specific events (cdc2/H1 kinase activation, H1 superphosphorylation, mitosis-specific H3 phosphorylation and chromatin condensation) induced by OA are sequentially associated. The changes appear to reflect a molecular mechanism similar to that operating in normal mitosis.

Adenine↗

PubMed1990

Purification and characterization of growth-associated H1 histone kinase from Novikoff hepatoma cells.

Growth-associated H1 histone kinase, a homolog of the yeast cdc2+/CDC28 protein kinases that control entry into mitosis, is a chromatin-bound cyclic nucleotide-independent enzyme found only in growing cells. In a procedure involving salt extraction of chromatin, ammonium sulfate precipitation, and three chromatographic steps, the enzyme has been purified greater than 10,000-fold from Novikoff hepatoma cells. Enzyme purified by this procedure catalyzes the transfer to H1 histone of 2.7 mumol of phosphate/min/mg, a specific activity within the range of those reported for a number of homogeneous or nearly homogeneous protein kinases. Further purification to near homogeneity was achieved by an additional step of sucrose density gradient fractionation. Enzyme activity in the sucrose gradient is associated with two polypeptides of apparent Mr 60,000 and 33,000 on sodium dodecyl sulfate-gel electrophoresis. Substrate specificity studies show that in addition to H1, proteins with H1-like structure and function including histone H1(0), the erythrocyte-specific H5 histone, and the testis-specific H1t histone are phosphorylated. Nucleosome core histone H3, high mobility group proteins 1, 2, 14, and 17, protamine, casein, and ribosomal protein S6 are not substrates.

Animals↗

PubMed1990

Cyclin is a component of maturation-promoting factor from Xenopus.

Highly purified maturation-promoting factor (MPF) from Xenopus eggs contains both cyclin B1 and cyclin B2 as shown by Western blotting and immunoprecipitation using Xenopus anti-B-type cyclin antibodies. Immunoprecipitates with these antibodies display the histone H1 kinase activity characteristic of MPF, for which exogenously added B1 and B2 cyclins are both substrates. Protein kinase activity against cyclin oscillates in maturing oocytes and activated eggs with the same kinetics as p34cdc2 kinase activity. These data indicate that B-type cyclin is the other component of MPF besides p34cdc2.

Adenosine Triphosphate↗

PubMed1977

Mechanism of translational control by hemin in reticulocyte lysates.

The formation of translational inhibitor (active eIF-2 kinase) from proinhibitor (inactive eIF-2 kinase) in reticulocyte lysates, known to be controlled by hemin, can, as we recently reported, be induced by 3':5'-cyclic AMP(cAMP)-dependent protein kinase (ATP:protein phosphotransferase, EC 2.7.1.37) or its catalytic subunit. We find that in crude preparations from rabbit reticulocyte lysates, hemin inhibits the conversion of proinhibitor to inhibitor catalyzed by endogenous cAMP-dependent protein kinase upon addition of cAMP, but not that caused by the addition of free protein kinase catalytic subunit. Hemin prevents the binding of cAMP to the regulatory subunit of cAMP-dependent protein kinase and blocks the cAMP-induced dissociation of regulatory and catalytic subunits of the enzyme whereby the enzyme is inactivated. The mechanism by which hemin prevents the formation of the inhibitor and maintains protein synthesis in reticulocyte lysates is thus explained.

Animals↗

PubMed1990

The topoisomerase II inhibitor VM-26 induces marked changes in histone H1 kinase activity, histones H1 and H3 phosphorylation, and chromosome condensation in G2 phase and mitotic BHK cells.

We have examined the effects of topoisomerase inhibitors on the phosphorylation of histones in chromatin during the G2 and the M phases of the cell cycle. Throughout the G2 phase of BHK cells, addition of the topoisomerase II inhibitor VM-26 prevented histone H1 phosphorylation, accompanied by the inhibition of intracellular histone H1 kinase activity. However, VM-26 had no inhibitory effect on the activity of the kinase in vitro, suggesting an indirect influence on histone H1 kinase activity. Entry into mitosis was also prevented, as monitored by the absence of nuclear lamina depolymerization, chromosome condensation, and histone H3 phosphorylation. In contrast, the topoisomerase I inhibitor, camptothecin, inhibited histone H1 phosphorylation and entry into mitosis only when applied at early G2. In cells that were arrested in mitosis, VM-26 induced dephosphorylation of histones H1 and H3, DNA breaks, and partial chromosome decondensation. These changes in chromatin parameters probably reverse the process of chromosome condensation, unfolding condensed regions to permit the repair of strand breaks in the DNA that were induced by VM-26. The involvement of growth-associated histone H1 kinase in these processes raises the possibility that the cell detects breaks in the DNA through their effects on the state of DNA supercoiling in constrained domains or loops. It would appear that histone H1 kinase and topoisomerase II work coordinately in both chromosome condensation and decondensation, and that this process participates in the VM-26-induced G2 arrest of the cell.

Animals↗

PubMed1985

Protein phosphorylation in a tetradecanoyl phorbol acetate-nonproliferative variant of 3T3 cells.

The 3T3-TNR9 cell line is a variant of Swiss 3T3 cells which does not respond mitogenically to tumor promoters, but does respond mitogenically to epidermal growth factor, fibroblast growth factor, and serum. To elucidate differences between tumor promoters and polypeptide mitogens in the pathway(s) of mitogenesis which might be responsible for the nonresponsiveness of the 3T3-TNR9 cells, we have examined in these cells the early protein phosphorylation events known to be associated with mitogenesis in the parental 3T3 cells. We find that the 3T3-TNR9 cells display levels of tetradecanoyl phorbol acetate binding and of a calcium- and phospholipid-dependent protein kinase activity which are at least the equal of those seen in the parental 3T3 cells, implicating some postreceptor event in the nonmitogenic phenotype. In addition, we find that phosphorylation of the epidermal growth factor receptor and of 80-kDa and 22-kDa proteins, as well as the tyrosine phosphorylation of a 42-kDa protein, all proceed normally in the nonmitogenic variant, even though these phosphorylations must depend on the activation of different kinases. Thus, all these early phosphorylation reactions are intact in the 3T3-TNR9 cells. Although these phosphorylations may be necessary, they clearly are insufficient to trigger mitogenesis.

Animals↗

PubMed1976

Characterization of protein phosphokinase activities in horse thyroid nuclei.

The distribution of protein phosphokinase (EC 2.7.1.37) activities has been established in horse thyroid nuclei. The presence of several enzyme activities has been demonstrated, two of which are clearly distinct. The first one acts on histone as substrate and is activated by cyclic AMP. Physico-chemical properties of this nuclear cyclic AMP-dependent histone kinase and of the cytosol histone kinase are different, demonstrating the absence of a contamination from the cytosol. The second enzyme acts on casein as substrate and is not stimulated by cyclic AMP POR CYCLIC GMP. The findings are consistent with the observation of thyrotropin stimulation of histone phosphorylation in thyroid nuclei.

Animals↗

PubMed1992

Estrogen modulates Ca(2+)-independent lipid-stimulated kinase in the rabbit corpus luteum of pseudopregnancy. Identification of luteal estrogen-modulated lipid-stimulated kinase as protein kinase C delta.

Rabbit corpora lutea were tested for the presence of phosphorylative responses sensitive to estrogen. Luteal Ca(2+)-independent lipid-stimulated kinase activity was detected by phosphorylation of the endogenous substrate, p76. Estrogen treatment, by way of estradiol-17 beta implant, increased levels of the lipid-stimulated phosphoprotein 2-3-fold throughout pseudopregnancy. Midpseudopregnant rabbit luteal extracts were further evaluated to determine the identity of the lipid-stimulated kinase. Results of low pH-activated phosphorylation were consistent with the identification of p76 as an autophosphorylated member of the protein kinase C (PKC) family. Partial purification of the luteal lipid-stimulated kinase was performed using sequential DEAE-cellulose/hydroxylapatite chromatographies and using gel filtration. Western immunoblot with type-specific anti-PKC delta antiserum showed coelution of kinase p76 activity with immunoreactive PKC delta. Immunoblot analysis confirmed that luteal levels of PKC delta were increased by estrogen treatment.

Animals↗

PubMed1977

Protein kinases in brown adipose tissue of developing rats. Electrophoretic separation and assay of soluble protein kinases on polyacrylamide gels and a study of their properties and changes during development.

Protein kinase activity was detected and assayed directly on polyacrylamide gels after disc electrophoresis of the 100,000 X g supernatant fraction of brown adipose tissue of infant rats. Nine major bands of activity were detected, eight of which could be stimulated by cAMP or inhibited by the cAMP-dependent protein kinase inhibitor protein. This electrophoretic technique revealed heterogeneity in the cAMP-dependent protein kinase activity eluted from DEAE-cellulose by high concentrations of salt, but not in the peak of activity eluted by low concentrations of salt. The catalytic properties and substrate specificities of the kinases in the various bands were studied while the enzymes were still in the gels. The activity in each band differed from each of the others in at least one of these properties. The activities of the protein kinases in brown fat changed as the animals grew, and each band exhibited a distinct and unique developmental pattern. The major changes in kinase activities occurred in the immediate post-parturition period, then at 15 days after birth and at weaning. These developmental stages coincide with the periods during which the tissue undergoes changes in the rate of its proliferation, differentiation, and functional activity.

Adipose Tissue, Brown↗

PubMed1985

Calcium-activated, phospholipid-dependent protein kinase activity and protein phosphorylation in HL60 cells induced to differentiate by retinoic acid.

Treatment of human promyelocytic (HL60) cells with retinoic acid for at least 48 h causes differentiation to more mature myeloid forms. Prior to commitment of cells to the myeloid pathway there is a marked increase in cytosolic calcium-activated, phospholipid-dependent protein kinase activity. This increase does not result from an intracellular redistribution of the enzyme. Concomitant with the increased enzyme activity there is enhanced phospholipid-dependent phosphorylation of proteins of 29, 49, 52, 58, 68, 69, 120, 170, 200 and 245 kDa.

Calcium↗

PubMed1991

Assembly/disassembly of the nuclear envelope membrane: cell cycle-dependent binding of nuclear membrane vesicles to chromatin in vitro.

Dissociation and association of membranes with chromatin at the beginning and end of mitosis are critical in controlling nuclear dynamics during these stages of the cell cycle. Employing purified membrane and cytosolic fractions from Xenopus eggs, a simple assay was developed for the reversible binding of nuclear membrane vesicles to chromatin. We have shown, using phosphatase and kinase inhibitors, that membrane-chromatin association is regulated by a phosphatase/kinase system. In interphase, the balance in this system favors dephosphorylation, possibly of a membrane receptor, which then mediates chromatin binding. At mitosis the membrane receptor is phosphorylated, causing release of chromatin-bound membrane. Purified MPF kinase does not directly cause membranes to dissociate from chromatin. Rather, binding of membranes to chromatin at mitosis appears to be regulated indirectly by MPF through its action on a phosphatase/kinase system that directly modulates the phosphorylation state of a nuclear membrane component.

Animals↗

PubMed2005

Inducible covalent posttranslational modification of histone H3.

The physiological state of a eukaryotic cell is determined by endogenous and exogenous signals, and often the endpoint of the pathways that transmit these signals is DNA. DNA is organized into chromatin, a nucleoprotein complex, which not only facilitates the packaging of DNA within the nucleus but also serves as an important factor in the regulation of gene function. The nucleosome is the basic unit of chromatin and generally consists of approximately two turns of DNA wrapped around an octamer of core histone proteins. Each histone also contains an accessible N-terminal tail that extends outside the chromatin complex and is subject to posttranslational modifications that are crucial in the regulation of gene expression. Two distinct categories of histone posttranslational modification have been observed: (i) inducible or stimulation-dependent and (ii) mitosis-dependent. Stimulation by mitogens or stress leads to rapid transient posttranslational modifications of histones, in particular histone H3, which are mechanistically and temporarily distinct from modifications associated with mitosis. This Review focuses mainly on the inducible phosphorylation of histone H3 brought about by different stimuli, such as epidermal growth factor, 12-O-tetradecanoylphorbol-13-acetate, arsenite, or ultraviolet radiation. We examine the most recent, and at times controversial, research data concerning the identity of the histone H3 kinases responsible for this phosphorylation. In addition, the interdependence of phosphorylation and acetylation will be discussed in light of data showing patterns of inducible modification at specific genes.

Acetylation↗